Skip to content


  • Review
  • Open Access

Neural and mesenchymal stem cells in animal models of Huntington’s disease: past experiences and future challenges

  • 1Email author,
  • 2,
  • 3 and
  • 4
Stem Cell Research & Therapy20156:232

  • Published:


Huntington’s disease (HD) is an inherited disease that causes progressive nerve cell degeneration. It is triggered by a mutation in the HTT gene that strongly influences functional abilities and usually results in movement, cognitive and psychiatric disorders. HD is incurable, although treatments are available to help manage symptoms and to delay the physical, mental and behavioral declines associated with the condition. Stem cells are the essential building blocks of life, and play a crucial role in the genesis and development of all higher organisms. Ablative surgical procedures and fetal tissue cell transplantation, which are still experimental, demonstrate low rates of recovery in HD patients. Due to neuronal cell death caused by accumulation of the mutated huntingtin (mHTT) protein, it is unlikely that such brain damage can be treated solely by drug-based therapies. Stem cell-based therapies are important in order to reconstruct damaged brain areas in HD patients. These therapies have a dual role: stem cell paracrine action, stimulating local cell survival, and brain tissue regeneration through the production of new neurons from the intrinsic and likely from donor stem cells. This review summarizes current knowledge on neural stem/progenitor cell and mesenchymal stem cell transplantation, which has been carried out in several animal models of HD, discussing cell distribution, survival and differentiation after transplantation, as well as functional recovery and anatomic improvements associated with these approaches. We also discuss the usefulness of this information for future preclinical and clinical studies in HD.


  • Quinolinic Acid
  • Medium Spiny Neuron
  • Mesenchymal Stem Cell Transplantation
  • Express Major Histocompatibility Complex Class
  • mHTT Protein


Huntington’s disease (HD) is believed to be due to a significant loss of medium spiny neurons in the brain. Main treatment efforts have, therefore, been focused on obtaining new medium spiny neurons to replace the damaged ones. One single transplantation of human fetal striatal tissue into brains of a small number of HD patients provided short-term improvement in both movement and psychological symptoms [1]. Tissue taken from aborted fetuses, however, offers only a very limited quantity of cells, which cannot be purified or improved. Therefore, alternative valuable sources, such as in vitro cultured, expanded and purified neural stem cells (NSCs)/precursor cells and mesenchymal stem cells (MSCs) are of great interest. In vitro models of HD have been developed and used in HD studies and in drug screening for HD [2]. It is hard to evaluate the effect of cell therapy in vitro, however, since it requires cell interaction of graft with host cells and tissues. The present review will provide a short description of HD degenerative nervous system disorder symptoms, causes, and current treatments, as well as recent achievements in animal studies employing NSCs/progenitor cells or MSCs in chemical and transgenic animal HD models in order to critically evaluate the use of the transplantation of these cells in HD treatment.

Huntington’s disease

HD is an inherited, autosomal-dominant, neurodegenerative disorder that results from the expansion (36 or more repeats) of a sequence of three DNA bases, cytosine-adenine-guanine (CAG), within exon 1 of the huntingtin (HTT) gene [35]. CAG repeat length in the mutant allele accounts for approximately 70 % of the variability in age of onset of HD, while the number of CAG repeats in the normal allele does not modify the age of onset [6, 7]. Triplet repeat length also influences disease progression, even after controlling for age of onset [8]. HD affects all races [9] and shows a stable prevalence in most populations of white people, which is of about 5 to 7 affected individuals per 100,000 [10]. The mean age of onset of HD is approximately 40 years; however, the disease may occur from infancy to the ninth decade of life [11]. Median survival time varies between 15 and 20 years from onset [12].

Clinical features of HD include progressive motor dysfunction, cognitive decline and psychiatric disturbance, probably caused by both neuronal dysfunction and neuronal cell death [12]. Despite its widespread distribution, mutant HTT (mHTT) protein causes selective neurodegeneration and neuronal loss, which occur preferentially in the striatum and in deeper layers of the cortex at early stages of HD [13, 14]. In advanced stages of the disease, many other brain regions can be affected as well, such as the globus pallidus, thalamus, hypothalamus, subthalamic nucleus, substantia nigra and cerebellum [1518]. Because of neurodegeneration, HD patients present typical involuntary movements called chorea (dance-like movements), manifested by spontaneous and transient muscle contractions [19, 20].

Huntington’s disease and neuronal cell loss

At a molecular level, HD is characterized by progressive loss of GABAergic medium spiny neurons, which constitute 95 % of all striatal neurons. As the disease progresses, neurodegeneration becomes most prominent in the neostriatum, commonly referred to as the striatum, which also includes the caudate nucleus and putamen. Striatal atrophy occurs in 95 % of HD brains, with a mean volumetric decrease of brain matter of 58 % [14, 21].

mHTT protein is thought to cause cellular dysfunction, neurodegeneration and associated clinical features primarily through a toxic gain of function [13]. Although the physiological role of normal HTT remains unidentified, many proteins are known to interact with HTT, such as brain-derived neurotrophic factor (BDNF), and this binding may be associated with HTT function [22]. HTT is normally expressed at highest levels in the brain, particularly in the cerebral cortex (layers II and V) and the striatum [23, 24]. HTT is also expressed in peripheral tissues, contradicting the restricted and regional pathology of HD [25]. HTT is mostly a cytoplasmic protein, though it is also found at low levels in the nucleus in both neuronal and non-neuronal cell types in HD [2628]. Regarding mHTT, the pathogenic process associated with polyGln expansion may involve an interaction with other proteins or multimerization to build large insoluble aggregates in the striatum and the cortex of HD patients [14, 2934]. Aggregates alter cell function by sequestering normal HTT [35], transcription factors [36], and transport proteins [37], ultimately leading to cell death. More recently, the accumulation of mHTT protein in the extracellular matrix in the brain of HD patients and in vitro spreading of these proteins from cell to cell have also been demonstrated [38, 39].

Huntington’s disease and brain-derived neurotrophic factor

The susceptibility of striatal neurons to atrophy in HD has been linked to nerve growth factors such as BDNF, which is a small dimeric protein expressed in the adult mammalian brain and has been shown to promote the survival of all major neuronal types and differentiation of striatal neurons [4042]. The use of BDNF as a biomarker is still debated by the scientific community. Some reports show decreased levels of BDNF in the striatum and plasma of HD patients [43] while other studies show that BDNF gene transcription (mRNA) and protein plasma levels are variable in peripheral blood in HD patients and are not, therefore, good biomarkers for predicting HD onset [44]. However, experimental preclinical studies show that BDNF has an important role in neurodegenerative diseases [4548]. As a neurotrophic factor, BDNF is vital for the growth and survival of neurons and glia. Thus, the promotion of endogenous BDNF upregulation may be key to neurodegenerative disease treatment [49]. Indeed, MSC transplantation into HD patients can serve as an alternative strategy to increase exogenous and endogenous BDNF expression [4547], as has been shown, for instance, in subpopulations of human MSCs [50].

The immune system, inflammation and Huntington’s disease

A large body of evidence indicates that neuroinflammation has a pivotal role in the development of several neurodegenerative diseases [51, 52]. Yet the exact underlying inflammatory mechanisms and the definitive impact of the innate and adaptive immune systems in HD pathology are still not fully understood. Different reports have previously demonstrated peripheral immune system dysfunction in HD, including an increase in innate immune system plasma proteins, such as complement factors and cytokines, several of which are associated with disease progression [5355]. Many of the inflammatory cytokines and chemokines found at elevated concentrations in HD patient plasma (mainly interleukin (IL)6, tumor necrosis factor (TNF) alpha and IL8), appear to originate from hyperactive monocytes [56, 57]. The pro-inflammatory cytokines IL6 and TNF are significantly increased in the striatum, plasma and cerebrospinal fluid in mouse models and in symptomatic as well as presymptomatic HD patients. This anomalous immune activation could be a target for future treatments aimed at slowing down HD progression [51, 52]. mHTT interaction with the key kinase of the nuclear factor kappa B (NFKB) pathway—the inhibitor of kappa B kinase—has been shown to be one of the causes of increased cytokine production in primary HD immune cells in humans, via increased activation of the NFKB signaling cascade upon stimulation with lipopolysaccharide. Elevated cytokine and chemokine levels found in HD patients correlate with disease progression and can be detected as early as 16 years before disease onset [54, 56, 58]. Patient blood cytokine composition and expression levels may be useful to establish the initial moment of therapeutic intervention. Patient blood signatures may also provide insights into the effects of HD on the brain, as well as serve as biomarkers of disease progression [59].

Animal models of Huntington’s disease

It is of major concern that preclinical studies of neurodegenerative disease have failed to predict efficacy in the clinic. In some cases, this is a consequence of inappropriate use of the model system [60]. The models most frequently used in preclinical and academic studies are chemical and transgenic HTT fragment models, and most studies use chemical models for inducing HD, whereby HD-like symptoms are induced by quinolinic acid (QA) [6167] or 3-nitropropionic acid (3-NP) [68, 69]. QA can be found endogenously, where it binds and activates the N-methyl-D-aspartate receptor, which is a glutamate receptor and ion channel protein found in nerve cells. At high concentrations it is neurotoxic by over-exciting the same receptors, eventually leading to neuronal cell death [70]. QA is used to induce neurodegeneration in animal models, including HD. 3-NP is also used to induce neurotoxicity via oxidative stress in striatum neuronal mitochondria. The effect is acute and variable and it depends on the animal, causing weight loss, lethargy, loss of motor control and atrophy in the striatum associated with neurodegeneration and death. Neither of these two chemical models reproduces the molecular events of neurodegenerative diseases and, in particular, of HD [71].

In preclinical studies of drugs for treating HT, the HTT fragment transgenic models are most widely used. These include mouse models such as N1T1-82Q2, R6/2, and R6/2-J2, all of which have a short mutated amino-terminal fragment of human HTT. These mouse models are all generated by the expansion in the CAG repeat of the first exon of HTT, causing symptoms similar to those observed in HD patients [62, 72] such as HTT aggregation, jerky movements and striatal atrophy [73]. The R6/2 andR6/2-J2 models have a well-characterized homogeneous phenotype and the advantage that it is possible to perform survival studies in a short time (3 months) [72]. N171-82Q mice have a longer HTT amino-terminal fragment than R6/2 mice, with 82 polyglutamines, and the N171-82Q phenotype is similar to, but less severe than, that of R6/2 and R6/2-J2 mice [74]. A variety of transgenic animal models of HD have been established and provide important insight into the pathogenesis of HD, but it is important to choose appropriate models in the specific case of evaluating the effects of stem cell transplantation. For instance, models that develop the disease quickly are adequate for short-term treatment studies, whereas genetic models that develop HD slower and for longer periods are best for the evaluation of long-term treatments. Complete information about HD animal models has already been published [75].

Stem cells in Huntington’s disease animal models

As mentioned above, one of the therapeutic approaches to HD is the use of stem cell-based transplantation. Here we discuss two main strategies of HD stem cell-based therapies: the use of NSCs/progenitor cells (Table 1) and the use of MSCs (Table 2). Generally, experimental protocols vary with regard to the HD animal model used, including differences in the origin of transplanted stem cells, the duration of in vitro stem cell expansion, the number of stem cell passages, expression of stem cell markers, cryopreservation, quantity of cells for transplantation, route of administration, time taken between transplantation and analysis, disease recovery, labeling and tracking of transplanted cells, evaluation of end-point of stem cell migration and differentiation after transplantation, and so on. Each of these aspects has their advantages and disadvantages, many of which are discussed in this review.
Table 1

Neural stem/progenitor cell transplantation in animal models of Huntington’s disease


Cell marker expression

Cell passage

Cell marker (visual)

Cell number and time of injection

Growth factor expression


Time of analysis

Behavior/ striatal volume

Cell distribution/ survival

Cell differentiation

Cell migratory activity

Conclusions and references

Human fetal cortex stem cells (12 weeks post-conception)

Not specified

Neurospheres 12 weeks in culture


200,000 cells; striatum 1 week after QA


QA rat

8 weeks post-graft

CNTF+ cells or CNTF– cells demonstrated significant improvement over the 8 weeks; increased striatal volume

Robust survival of HN and Ki-67-positive cells: striatum, GP, EPN, and SNpr

Co-localization of GFAP + HN in striatum only

CNTF– stronger migratory activity; GP, EPN, and SNpr

Striatal transplants of human fetal stem cells in HD rat QA model elicit behavioral and anatomical recovery [65]

Immortalized huNSC lines from fetal telencephalon tissue

ABCG2+, nestin+, vimentin+

No data

Lac Z

1 × 106; right striatum 1 week prior to damage induction or 12 h after

BDNF secretion

3-NP rat

2 weeks post-graft

1 week prior to damage induction: significantly improved motor performance and reduced damage to striatal neurons. 12 h after: no improvement in motor performance

Striatum; robust survival

Positive for beta-tubulin III, GFAP, calbindin, GAD

Limited migration to graft core in striatum

Improved motor functions and reduced cellular damage, neurotrophic support by secreted BDNF. Differentiation of huNSCs to GABAergic neurons, but not cholinergic or dopaminergic neurons [69]

Immortalized huNSC line (15 weeks gestation)


~24 passages

Lac Z, BrdU

5 × 106 cells; IV transplant; tail vein; 7 days post-QA

Not specified

QA rat

From 2 up to 8 weeks post-graft

Significantly greater striatal volume

Predominantly lesion side of hemisphere; additionally renal cortex, spleen and epithelium of bronchioles

BrdU+/GFAP+/NeuN+; BrdU+/parvalbumin–/DARRP-32–/calbindin–

3 weeks after : X-gal + cells in striatum: in the parenchyma and around vessels

Intravenously transplanted NSCs migrate to the lesion site, reduce cellular damage, and induce functional recovery. Differentiate into neurons and glia, NTD [63]

huNSCs: same as in Lee et al. [63]; 2n = 46, XX

Nestin+, vimentin+

~24 passages or more

Lac Z

1 × 105 intraventricular; 10 × 105 IV

Not specified

QA rat

3 weeks post-graft

No data

Predominantly lesion side of hemisphere

No data

From 2 to10 weeks X-gal + cells in striatum: in the parenchyma and around vessels

NSCs migrate into the striatum, from both ventricle or systemic circulation, NTD [64]

Immortalized mNSCs: MHP36 cells

Not specified

Not specified


~400,000 cells; striatum

Not specified

3-NP rat

14 weeks post-graft

No effect on striatal volume

Predominantly populated areas of damage

Endogenous glial differentiation; PKH26 cell differentiation into astrocytes and neurons

Graft in the region of neuronal loss and striatum, no migration

MRI. Partial recovery of learning in water maze. No effect on striatal volume. Implanted cells did not penetrate through the glial scar to reconstruct lost tissue [68]

Allotransplant of striatal cells: a) neurospheres; b) cell suspension

Not specified

Neurospheres third to sixth passage


40,000 cells; striatum; 2, 7, and 14 days after QA

Endogenous BDNF expression stable before and after cell transplant

a,b) QA mice; c) R6/2 mice

14 days and 3 months post-graft

Not specified

a) 2 days after QA: significant graft survival

a) GFAP+ up to 3 months

Better migration of the cells in R6/2 versus QA

a) Best survival: combination of early transplantation + neurospheres

b) 7 and 14 days after QA: reduced graft survival

b) Undifferentiated

b) Astroglia and microglia activation in the striatum after injection of QA

After 3 months the graft volume was reduced [62]

c) 3 to 4 weeks survival time

Adult SVZ-derived rNPC


Neurospheres; suspension; passage not specified

BrdU-labeled cells

180,000 cells; striatum

Not specified

QA rat

8 weeks post-graft

Reduce functional impairment

12 % graft survival

GFAP+, NeuN+, DARPP-32+, GAD67+

Migrated extensively; striatum

Neural progenitor cell transplantation reduces rotational asymmetry and impairment of spontaneous exploratory forelimb use [66]

Embryonic LGE and MGE-derived rNSCs

Nestin+, GFAP+

Passage 2

PKH26, Hoechst, TOTO-3

100,000 cells; striatum


QA rat

3 or 8 weeks post-graft

Not specified

3 weeks



SCF increased expression [61]

Adult SVZ-derived rNPCs pretreated with LiCl


Cultured in vitro 14 days before transplant

BrdU-labeled cells

150,000 cells; striatum; 21 days after QA

Not specified

QA rat

12 weeks post-graft

Acceleration of sensorimotor function recovery

Increased survival

GFAP+, NeuN+, DARPP-32+, GAD67+

Migration in striatum

LiCl priming did not alter the maximal distribution of NPCs across the striatum, while augmenting transplant efficiency and accelerating sensorimotor function outcome in vivo [67]

3-NP 3-nitropropionic acid, BDNF brain-derived neurotrophic factor, BrdU bromodeoxyuridine, CNTF ciliary neurotrophic factor, DARPP-32 dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa, EGFP enhanced green fluorescent protein, EPN entopeduncular, GABA gamma aminobutyric acid, GAD glutamate decarboxylase, GFAP glial fibrillary acidic protein, GP globus pallidus, HD Huntington’s disease, HN human-specific marker to nuclear antigen, huNSC human neuronal stem cell, IV intravenous, LacZ beta galactosidase, LGE lateral ganglionic eminence, MGE medial ganglionic eminence, mNSC murine neuronal stem cell, MRI magnetic resonance imaging, NPC neuronal progenitor cells, NSC neuronal stem cell, NTD no tumorigenesis detected, QA quinolinic acid, rNPC rat neuronal progenitor cells, rNSC rat neuronal stem cell, SCF stem cell factor, SNpr substantia nigra pars reticulate, SVZ subventricular zone, X-gal 5-bromo-4-chloro-3-indolyl-β-D-galatopyranoside

Table 2

Mesenchymal stem cell transplantation in animal models of Huntington’s disease


Cell markers


Cell labeling

Cell number/inoculation site, inoculation time

Growth factor expression

Animal model/ age

Time of analysis

Animal behavior/ striatal volume

Cell distribution/ survival

Cell differentiation

Cell migratory activity

Conclusions and references

MSCs from mUCB


Low: 3 to 8

Hoechst 33,358

400,000 cells per hemisphere


R6/2, 5 weeks mice


Significant differences were observed between R6/2 and high-passage mUCB MSCs at 10 weeks of age

Not specified

No differentiation

Not specified

Transplantation of low-passage mUCB MSCs did not confer significant motor benefits. Limb-clasping was not observed [122]


High: 40 to 50



MHC class I

MHC Class II


Not specified

Not specified


5 × 105 or 1 × 106; striatum

Not specified

QA rat

7 days after lesion

Not specified

Not specified

Not specified

Blood vessels and lateral ventricles in both hemispheres

Reduced brain damage and enhanced striatal expression of FGF-2 [125]


Not specified

Not specified

Hoechst 33,258

200,000 or 400,000 cells per hemisphere; 28 days after 3-NP

mRNA: BDNF, collagen type I and fibronectin

3-NP rat

From 72 h to 14 days post-graft

Behavior improvements

No distribution

No differentiation

No migration

Increased mRNA:BDNF, collagen type I and fibronectin. Neuroprotective effect. Behavior improvement [126]

Human AT-MSCs; hypoxia

Positive: nestin, NG2, KDR, FLT1, and CD34

Not specified


5 × 105cells; bilateral striatum


R6/2; 8.5 weeks mice

4 weeks after injection

Slowed behavioral deterioration

Not specified

Tuj-1 GABAergic neurons. PGC-1α master regulator of mitochondrial biogenesis increased in ASC treated mice


Reduced striatal degeneration and formation of ubiquitin-positive aggregates. Behavior improvement [123]

Negative: neurofilament O4

Human AT-ASCs; hypoxia

Same as above

Not specified

Vybrant DiO

106 cells; striatum after injection of QA

Same as above

QA mice; 8.5 weeks

Same as above

Significant improvement in apomorphine-induced rotation tests

Not specified

BDNF, calbindin, GABA, GAD—neuronal enzyme

Near transplantation locus forming a lump

Neuroprotective effect. Behavior improvement [123]

Adult rBM-MSCs

Nestin+, GFAP+, SCF/c-kit+

Passage ≥10

PKH26, Hoechst and TOTO-3

100,000 cells; striatum


QA rat

3 weeks or 8 weeks post-graft

Not specified



Limited; striatum

SCF increased expression [61]

Human BM-MSCs

Positive: CD29, CD44, CD49c, CD49f, CD59, CD90, CD105, CD166

Early: 3 to 5


100,000 hMSCs; striatum

Not specified

N171-82Q mice

1, 3, 5, 7, 15, and 30 days post-graft

Decreased atrophy of the striatal volume

Survival: 15.1 % at 24 h; 4.5 % at 5 days; 0 % at 15 days

hMSCs are undifferentiated. Endogenous cell: NeuN, βIII tubulin

hMSCs recruit pre-existing neuronal cells to the striatum

Increased: FGF-2, CNTF, VEGF, NGF. Endogenous cell proliferation. Reduced striatal degeneration [96]

Negative: CD34, CD36, CD117, CD45

Human BM-MSCs; immortalized cell line

Not specified

Not applied

Bisbenzimide + TOTO3

200,000 cells per hemisphere

Not specified

WT mice

8 weeks post-graft

Not applied

Survival rate-significant


Human BM-MSC transplantation induces migration of endogenous neuroblast cells

Not specified [124]

Human BM-MSCs

Not specified

Not applied


200,000 cells per hemisphere

Not specified

QA mice

16 days post-graft

Improves: rotarod performance, striatum volume

Survival rate—significant. Reduced cell apoptosis

GFAP, NeuN, DARPP-32, F4/80 (macrophage and microglial marker)

Same as above

Neuroprotective effect. Behavior improvement. Reduced striatal degeneration [124]

Human BM-MSCs

Not specified

Not applied


200,000 cells per hemisphere

Not specified

R6/2-J2 mice

16 days post-graft

Improves: rotarod performance, striatum volume

Survival rate—significant. Reduced cell apoptosis

GFAP, NeuN, DARPP-32, F4/80

Same as above

Same as above [124]

3-NP 3-nitropropionic acid, ASC adult stem cell, AT-ASC adipose tissue-derived adult stem cell, AT-MSC adipose tissue-derived mesenchymal stem cell, BDNF brain-derived neurotrophic factor, bFGF basic fibroblast growth factor, BM-MSC bone marrow-derived mesenchymal stem cell, CNTF ciliary neurotrophic factor, DARPP-32 dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa, EGF epithelial growth factor, FGF-2 fibroblast growth factor 2, GABA gamma aminobutyric acid, GAD glutamate decarboxylase, GFAP glial fibrillary acidic protein, GFP green fluorescent protein, GM-CSF granulocyte-macrophage colony-stimulating factor, HGF hepatocyte growth factor, hMSC human mesenchymal stem cell, IGF-1 insulin-like growth factor 1, KDR kinase insert domain receptor, MHC major histocompatibility complex, MSC mesenchymal stem cell, mUCB mouse umbilical cord blood, NGF nerve growth factor, PDGF platelet-derived growth factor (alpha polypeptide), PGC-1α peroxisome proliferator-activated receptor-γ coactivator 1 α, QA quinolinic acid, rBM-MSC rat bone marrow-mesenchymal stem cell, SCF stem cell factor, VEGF vascular endothelial growth factor, WT wild type

Neural stem cells/progenitor cells

Fetal- or adult-derived NSCs/progenitor cells are considered an attractive source for cell therapy because they are already committed to neural differentiation. Primary cultures [62, 65] and fetus-derived immortalized cell lines [61, 63, 68, 69], as well as progenitor stem cells from central nervous system (CNS) brain tissues [66, 67], have been used in animal studies. NSCs/progenitor cells, when undifferentiated, express markers such as vimentin (present in migrating neural crest cells and in neural stem cells of the adult CNS) [64, 69], nestin (expressed predominantly in NSCs/progenitor neural cells) [61, 63, 64, 69], the transcription factor SRY (sex determining region Y)-box 2 (Sox2; known to be expressed at high levels in the neuroepithelium of the developing CNS) [66, 67], and other neuronal and glial markers, such as Abcg2 (ATP-binding cassette, sub-family G (WHITE), member 2) [69] and glial fibrillary acidic protein (Gfap) [61]. Such adult-derived NSCs/progenitor cells also express low levels of the major histocompatibility complex (MHC) class II antigens [76], and exhibit high survival rates when transplanted into normal adult rat brains [77, 78].

Neural stem cells/progenitor cells in vivo and the host immune system

Whether or not NSCs/progenitor cells, similarly to MSCs, exhibit therapeutic action—cell replacement and neuroprotection—the immunomodulatory effects of NSCs/progenitor cells still remain to be studied in depth [79]. Neuroprogenitor cells have a suppressive effect on T cells that is accompanied by a significant decrease in proinflammatory cytokines such as IL2, TNFα, and interferon-γ [80]. Moreover, NSCs/progenitor cells inhibit multiple inflammatory signals, as exemplified by the attenuation of T-cell receptor-, IL2-, and IL6-mediated immune cell activation and/or proliferation [81]. However, the transplantation of fetal NSCs/progenitor cells and embryonic stem cell-derived NSCs/progenitor cells into patients and in mice with Parkinson’s disease revealed an immune response [82, 83], which may be explained by the presence of microglia or astroglia in the primary cell suspension, which strongly express MHC class II molecules [84].

Routes of neural stem cell/progenitor cell transplantation

In the majority of studies carried out with HD models, NSCs/progenitor cells are transplanted directly into the striatum, where they show good survival and distribution predominantly in the damaged areas of the brain [6163, 6569]. However, these cells demonstrate limited migration in scar tissue [68]. In contrast, cells injected in the tail vein are associated with a wider brain distribution [63] and are found in the lesioned brain hemisphere, especially near blood vessels and in the parenchyma. Additionally, NSCs/progenitor cells are also found in peripheral organs, such as in the renal cortex, the spleen and the bronchiole epithelium [63] (Table 1). Intravenous (IV; systemic) administration of NSCs/progenitor cells also shows cell retention in lung capillaries directly post-injection, resulting in inflammation and apoptosis in lung tissue [85].

Neural stem cells/progenitor cells in Huntington’s disease animal models

NSC/progenitor cell transplantation has been carried out in several animal studies for treatment of HD, as summarized in Table 1. Different cell sources and preparation methods have been used: single cell suspension of primary culture of NSCs/progenitor cells [61, 62, 67] or neurospheres formed by NSCs/progenitor cells derived from brain tissue [62, 65, 66]. Several studies did not evaluate the expression of specific NSC/progenitor cell markers before transplantation into the animal model [62, 65, 68] (Table 1). The number of cells and cell passages and the cell labeling for tracing vary between the studies (Table 1).

Data on the capacity of NSCs/progenitor cells to differentiate into neurons in vivo are controversial; most studies demonstrate differentiation into neurons and glial cells [62, 63, 6569], while a few report that transplanted cells remain undifferentiated [61, 62]. Glutamate decarboxylase (GAD)1 (also known as GAD67), is an important marker of neural differentiation in HD. It catalyzes the synthesis of gamma-aminobutyric acid (GABA), a neurotransmitter that promotes synaptogenesis and protection from neural injury. High GAD1 levels are, therefore, an important marker of recovery in HD patients. Parvalbumin and calbindin-D28k are calcium binding proteins expressed in GABAergic interneurons. The expression of these proteins was observed in four studies that used adult subventricular zone-derived rat NSC allotransplantation [66, 67] and immortalized fetal tissue-derived human NSC xenotransplantation [64, 69]. Expression of GAD1, calbindin-D28k and/or DARPP-32 (dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa) was observed in four studies [66, 67], while glial fibrillary acidic protein (GFAP) expression was seen in the majority of studies [62, 63, 6567, 69] (Table 1). In one study [63], which used IV injection of immortalized cell line-derived human NSCs, expression of early markers of neuronal differentiation was found 2 months post-graft.

For successful therapeutic use of NSCs/progenitor cells in HD, it is likely that they need to differentiate into functional neuronal cells that can aid patient recovery. Differences in cell biodistribution between neurospheres, which do or do not express ciliary neurotrophic factor (CNTF), has been observed in HD models. Neurospheres that lack expression of CNTF demonstrate better migration activity in comparison with those that express this factor [65]. The migration ability of NSCs/progenitor cells in the transgenic HD R6/2 model differed from that in a QA chemical model [62]. Moreover, neuronal differentiation into GABAergic and dopaminergic neurons was only observed when using cell allotransplantation in the QA model [66, 67] as opposed to the genetic model. Interestingly, one study demonstrated that neurospheres show better graft survival compared with cell suspensions, but differentiate to GFAP-positive cells, usually astrocytes, instead of neuronal cells [62]. This information is relevant for future stem cell-based therapies and should be thoroughly verified.

An important issue regarding cell transplantation is the possibility of induction of tumorigenesis. Only two studies have tested the tumorigenic potential of NSCs/progenitor cells in normal animals and did not find any type of pathology. The absence of tumorigenic potential is an extremely important characteristic of NSCs/progenitor cells that are to be used therapeutically. Considering that NSCs/progenitor cells are frequently isolated from embryo/fetal tissues, which are immature and commonly associated with tumorigenesis, further studies are needed to guarantee that NSC/progenitor cell transplantation is not tumorigenic [63, 64].

Although NSC/progenitor cell transplantation has been shown to be sufficient to induce moderate functional and anatomical recovery in chemical HD models, with increased striatal volume, reduced cellular damage and partly induced differentiation of NSCs/progenitor cells into glial cells and neurons [66, 67], there are still limitations to their therapeutic use. These limitations include ethical concerns regarding the source of NSCs/progenitor cells as well as the low quantities usually derived from these sources, which hinder their use and reliability.

Mesenchymal stem cells

MSCs are commonly found in bone marrow, umbilical cord and fat pads [8688]. They are responsible for tissue regeneration in cases of disease or injury throughout life. This function of MSCs is mediated by self-renewal and plasticity (the ability to produce diverse types of differentiated cells). MSCs can be isolated from the aforementioned tissues and are easily cultured; after obtaining a small number of cells from a patient, they can be rapidly multiplied in vitro and cryopreserved for future clinical applications.

MSCs are believed to be ‘cellular paramedics’ since they secrete a variety of bioactive molecules, such as cytokines, which have ‘trophic activities’ that can promote a regenerative microenvironment, and other molecules that contribute to reconstruction as immunomodulatory mediators and even by carrying molecules into damaged cells [89]. Autologous and allogeneic in vitro expanded MSCs transplanted into the recipient organism migrate to the injury site in response to chemotactic stimuli, and also induce migration of intrinsic (endogenous) MSCs to the same site from the surrounding environment. MSCs can act by reducing chronic inflammation, inhibiting apoptosis and scar formation and stimulating mitosis of tissue-intrinsic progenitors, thus remodeling the damaged tissue [90]. Due to these properties, MSCs are known as ‘medicinal signaling cells’ [89, 91, 92].

MSCs also stimulate angiogenesis, the process of new blood vessel formation, which is closely linked to neurogenesis, the process by which new nerve cells are produced. Blood vessels play an important role as a framework for neuronal progenitor cell migration toward the damaged brain region. Paracrine factors secreted by MSCs also reduce the destructive effects of oxidative stress. Using all these mechanisms of action, MSCs can significantly improve lesioned microenvironments that lead to restoration of the damaged tissue [9294]. According to recent publications, MSCs can repair neurodegeneration by secreting trophic factors and proteins that stimulate migration, differentiation and survival of intrinsic (endogenous) cells [89, 91, 92]. Among specific effects on nerve cells, these factors can promote axon extension, growth, and even cell attachment to substrate in vitro. Although there is evidence that MSCs promote cell growth and repair in the brain, it has not yet been definitively confirmed that MSCs can become mature nerve cells with the ability to signal, or communicate with, other nerve cells [9496].

Mesenchymal stem cells in vivo and the host immune system

Many experiments have been carried out in which MSCs are transplanted into other organisms of the same or of different species. These cells are not rejected because MSCs have very low levels of MHC class II proteins and lack MHC class I proteins and cannot, therefore, present exogenous antigens to the recipient (host) organism [97100]. As a result, they are perceived as endogenous. MSCs also interact with the host immune and inflammatory systems in other ways, as discussed below.

When human MSCs are labeled in order to track their migration and then injected into mice that have some type of tissue damage, they migrate evenly throughout the damaged tissues. These cells may or may not be present in the tissue for a substantial period of time, which depends on many factors, such as cell type, animal model, time of cell transplantation, and so on. The continued presence of MSCs is important, but not essential, in therapeutic treatments because it demonstrates the potential for positive long-term effects of transplantation. It is important to realize that the temporary presence of MSCs is not a result of the host immune response, since experiments in injured mice with and without functional immune systems yield the same results. Further investigations show that MSCs suppress the immune system and reduce inflammation [101]. In brain injury models, MSC treatment reduces the presence of microglia in the damaged brain and decreases the number of peripheral infiltrating leukocytes at the injured site by increasing anti-inflammatory cytokines [102]. In other words, MSCs can be transferred between organisms without eliciting immune rejection by the host, which renders them very good candidates for transplantation, immunosuppression and immunomodulation [100, 103107].

Routes of mesenchymal stem cell transplantation and penetration through the blood–brain barrier

A crucial issue in cellular therapies for HD is the route of MSC delivery into the brain, which has been approached in a number of different ways. Several administration routes have been proposed to deliver MSCs into the CNS, such as intracerebral (hemisphere or more precisely striatum), intrathecal, IV, intrathecal plus IV into the space surrounding the spinal cord, and even intranasal [108, 109].

The blood–brain barrier (BBB) is formed in early embryological development through complex multicellular interactions between immature endothelial cells and neural progenitors, neurons, radial glia, and finally pericytes, which share similar features with MSCs. It selectively controls molecular and cellular trafficking between the bloodstream and brain interstitial space, which is a concern when considering routes of drug and cell delivery to treat brain malignancies and neurodegenerative disorders. Systemically infused MSCs may be able to treat acute injuries, inflammatory diseases, CNS stroke and even brain tumors because of their regenerative capacity and ability to secrete trophic, immunomodulatory, growth or other engineered therapeutic factors. However, whether MSCs possess the ability to migrate across the BBB in vivo under both normal and pathological conditions remains poorly resolved [110]. Systemic infusion (that is, IV) of in vitro expanded MSCs is a minimally invasive and convenient procedure that is used in a large number of ongoing clinical trials: acute graft-versus-host disease [111], acute myocardial function [112, 113], liver disease [114] and multiple sclerosis [115]. Therefore, it is essential to verify whether transplanted MSCs can home to and engraft at ischemic and injured sites in the brain in order to exert their therapeutic effects. During brain inflammation and injury, the BBB becomes compromised, allowing cellular trafficking through the BBB, including leukocyte trafficking to sites of CNS inflammation, as has been well studied and extensively reviewed [116, 117]. Several recent studies suggest that adipose tissue- and bone marrow-derived MSCs may possess leukocyte-like activities that enable them to interact with and migrate across the BBB after injury or inflammation [110, 118120]. It is suggested that MSCs can transmigrate across the brain vascular endothelial monolayer through transiently formed inter-endothelial gaps [121]. Given that MSCs have this ability to transmigrate across the BBB, they can be administered IV, which is not as invasive as the intrathecal or intracerebral (for example, in striatum) routes [65].

Mesenchymal stem cells in Huntington’s disease animal models

The ‘simplicity’ with which MSCs can be obtained and cultured, as well as their unique trophic activities and the possibility of their transfer into the host without immune rejection, are the reasons why we are hopeful that MSCs may offer a promising way to develop treatments for neurodegeneration. Table 2 summarizes published data on MSC transplantation into HD animal models.

Note that none of the published HD animal studies used systemic (IV) MSC transplantation. Table 2 also shows the types of cells used as origin and pre-treatment. Allogeneic and xenogeneic, primary cultures and immortalized cell lines from bone marrow, adipose tissue and umbilical cord blood, grown under normal levels of oxygen (normoxia) and under low levels of oxygen (hypoxia), have been used [61, 96, 122125].

The majority of cells used in vivo in HD models are referred to as MSCs, multipotent stromal cells or adipose tissue-derived stem cells. However, most published articles do not demonstrate that the cells used present the typical MSC immunophenotype in accordance with the minimal criteria for defining multipotent mesenchymal stromal cells, as established by The International Society for Cellular Therapy [95]. Snyder and co-workers [96] are the only ones who show that, among other cell markers, the cells used in their study also express CD90 and CD105, which are considered markers of MSCs. While only one study reported that mouse umbilical cord blood (mUCB)-derived MSCs do not express MHC class II cell surface molecules [122], other authors did not provide such information. A few publications report that the cells used express neurotrophic factor genes, but they do not clarify whether the products of these genes are translated into protein [61, 122, 126] (Table 2).

All studies used cells at passages no higher than 10, excluding one study, which used mUCB-derived MSCs at passages 40 and 50 [122]. Interestingly, these authors observed that the expression of pluripotent stem cell markers, such as SSEA4 (stage-specific embryonic antigen 4), increases with the passages, as well as that transplantation of high-passage mUCB-derived MSCs confers significant motor benefits compared with that of low-passage mUCB-derived MSCs. However, the use of MSCs from later passages is not usual in animal and clinical studies due to chromosomal instability.

Cell doses per transplantation and cell tracer use vary between studies. Each has their advantages and disadvantages, as discussed in the ‘Neural stem cells/progenitor cells’ section of this review; taken together, however, they confirm that MSCs reach and engraft into the damaged areas of brain in HD animal models. These methods also show that the cell graft is mainly restricted to the striatum—the cells are found near the transplantation site, forming a lump, and show no or very limited migration. In one study, the authors observed that the cells are mainly localized near blood vessels and lateral ventricles in both hemispheres [125]. The low migration capacity of MSCs can be partly explained by application of the cells directly to the injured site [127], which does not provide stimulus for their migration due to the inflammation process that ensues, which is very chemoattractive for MSCs. This, for example, has been shown in cell transplantation in muscular dystrophy in the golden retriever model, whereby, after intramuscular transplantation, MSCs do not migrate from the region of local muscle application [87].

Different chemical (QA and 3-NP) and genetic models (R6/2-J2, N171-82Q, R6/2) of HD have been used in MSC transplantation studies (Table 2). There is no standardization with respect to time interval between MSC transplantation and analysis of results (Table 2). The studies which analyze survival of MSC post-transplantation note short-term survival of transplanted cells and reduction of apoptosis of intrinsic cells [61, 96, 124]. Most authors report that transplanted cells remain undifferentiated post-graft [61, 96, 122, 126], which supports the statement that MSC activity is similar to that of CNS microvascular pericytes [128]. These latter cells have critical and complex inductive, structural, and regulatory roles, interacting with other cell types of the neurovascular unit, especially endothelial cells and astrocytes [110]. On the other hand, several studies demonstrate expression of neuronal markers in transplanted cells, such as Rbfox3 (RNA binding protein, fox-1 homolog 3, also known as NeuN), which is a neuron-specific nuclear protein; however, NeuN appears to be devoid of immunoreactivity towards cerebellar Purkinje cells [129].

In general, all studies carried out in HD animal models using MSC transplantation observed behavioral and memory improvements, reduced brain damage and amelioration of striatal degeneration, and enhanced expression of several striatal growth factors. Most authors attribute these results to the neuroprotective effect of MSCs (Table 2).

Stem cells in Huntington’s disease clinical investigations

The prospect of using stem cells to intervene in neurodegenerative disease is promising. To date, however, only a small number of clinical trials has been undertaken, whereby fetal donor tissues have been transplanted into the striatum [130]. Cell therapies in HD are intended to protect neuronal populations that are susceptible to the disease and/or replace dysfunctional or dying neurons. Clinical progress in HD cell therapy has centered on establishing protocols for transplanting fetal-derived cells into the diseased striatum. This strategy is stimulating the development of stem cell therapy in the clinic and has been shown to provide patients with a period of several years of improvement and stability, but not with a permanent cure for the disease [131]. A long-term follow-up of patients over a 3- to 10-year postoperative period shows that fetal striatal allograft in HD is safe, although this study showed no sustained functional benefit [1]. The authors suggest that such a result is due to the small amount of cells that were grafted in this safety study compared with other reports of more successful transplants in patients with HD [1]. This obstacle can be overcome with new cell technologies, which allow stem cell in vitro expansion, while preserving their natural capacity for self-renewal and differentiation.


The animal studies discussed in this review agree that NSC/progenitor cell and MSC transplantation can be beneficial, with partial functional and anatomical recovery, reduced cell death, reduced brain damage, increased endogenous cell proliferation and even partial differentiation of transplanted cells towards neurons (summarized in Fig. 1). More importantly, studies have even demonstrated reduced formation of ubiquitin aggregates upon adipose cell-derived MSC transplantation into HD mice [123] or when NSC therapy is associated with trehalose administration [132]. However, several points still need to be considered and answered using animal models.
Fig. 1
Fig. 1

Effect of neural stem cells/progenitor cells and mesenchymal stem cell transplantation on Huntington’s disease etiology and progression. Huntington’s disease (HD) is caused by an expansion of (polyQ) repeats within the amino terminus of the huntingtin (HTT) protein, which promotes HTT aggregation and formation of intracellular inclusion bodies. These events lead to microglial activation, which correlates with striatal neuronal dysfunction and neuronal death as well as with reduced expression of striatal D1 and D2 receptors and of neurotrophic factors [136, 137]. In turn, striatal neuronal dysfunction correlates with cortex atrophy, motor deficits and cognitive deficits in HD patients. According to the most updated literature on HD, both neural stem cells (NSCs)/progenitor cells and mesenchymal stem cells (MSCs) improve motor coordination, behavior and memory. NSCs/progenitor cells and MSCs also seem to be able to reduce formation of HTT-ubiquitin aggregates. HD improvements occur as a result of NSC/progenitor cell and MSC transplantation through very similar mechanisms, such as immunomodulation, trophic properties, neurotrophic support and neuronal protection. These mechanisms are well known for MSCs and only marginally recognized for NSCs/progenitor cells [79, 94]. Until now, the great advantage of MSCs, in comparison with NSCs/progenitor cells, are their immunoprivileged properties, few or lack of ethical concerns regarding their origin, significant therapeutic quantities, non-teratogenicity (safety), as well as immunomodulation. Although in vivo differentiation of both cell types has been demonstrated, it is not clear if the number of differentiated cells is sufficient to justify all brain improvements found upon transplantation or whether changes are due to intrinsic cell regeneration. mHTT mutant huntingtin

It is worth mentioning that both the design of animal studies and the characterization of transplanted cells are poorly standardized and that this greatly complicates comparative analysis. In the future, an agreement between researchers must be reached in order to standardize marker use to enable study comparison and reproducibility.

It seems that NSCs/progenitor cells and MSCs can be used interchangeably. However, MSCs have an advantage over NSCs/progenitor cells in that there are fewer ethical considerations regarding their extraction and because they are easy to isolate and expand in vitro. Primary cultures of NSCs/progenitor cells are usually heterogeneous, containing many cell types, which makes characterization harder and experiments less reproducible. Moreover, MSCs are non-immunogenic, while neural stem/progenitor cells may require a co-application of an immunosuppression protocol (Fig. 1).

As to cell numbers (best dose) at transplantation, there does not seem to be any consensus. Fewer cells are probably best to avoid tissue damage upon transplantation. On the other hand, the population must be large enough to guarantee that sufficient cells can reach the area of tissue damage and promote recovery. Transplanted cells should be able to reproduce in the recipient organism while still undifferentiated, but their number should not be increased drastically in order to avoid carcinogenesis.

The administration route of stem cell transplantation should be revised, considering that local injections are extremely invasive and that NSCs/progenitor cells and MSCs do not show efficient migratory capacity, as extensively reviewed by Reyes and colleagues [133], among others [61, 87, 123, 126, 127, 133].

In chemical models, the cells are usually administered after HD induction with the drug, while, in transgenic animals, cell administration time depends on disease progression. Administration time should be adequately considered in order to derive the most benefit from the stem cell-based therapy.

So far, all animal and clinical study protocols for HD used only one course of cell transplantation. This is not compatible with the neurodegenerative character of the disease. In HD patients, the degenerative process is progressive and stem cell-based therapies should, therefore, be applied regularly. The point at which the therapy should begin and the time intervals between cell transplantations can vary significantly and are questions to be answered in future studies.

It is still unclear from animal studies how transplanted cells regulate the expression pattern of inflammatory cytokines and chemokines, as well as that of neurotrophic factors, which are also concerns that should be addressed before clinical trials.

Finally, HD therapy protocols using stem cells should be developed not only for treating the clinical onset of HD but also to prevent HD development [134]. The establishment of new methods to quantify mHTT in cerebrospinal fluid may facilitate the study of HD, since mHTT could potentially serve as a biomarker for the development and testing of experimental mHTT-lowering cell therapies for HD [135].



3-Nitropropionic acid


Blood–brain barrier


Brain-derived neurotrophic factor


Central nervous system


Ciliary neurotrophic factor


Dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa


Gamma aminobutyric acid


Glutamate decarboxylase


Glial fibrillary acidic protein


Huntington’s disease








Major histocompatibility complex


Mutant huntingtin


Mesenchymal stem cell


Mouse umbilical cord blood


Nuclear factor kappa B


Neural stem cell


Quinolinic acid


Tumor necrosis factor


Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

Laboratório de Genética, Instituto Butantan, 1500 Av. Vital Brasil, São Paulo, 05503-900, Brazil
Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, 455 Av. Dr. Arnaldao, São Paulo, 01246903, Brazil
CellAvita Ltd, 1470 Al. Santos, 9th floor, block 909, São Paulo, SP, 01418-100, Brazil
SoluBest Ltd, Weizmann Science Park, POB 4053 18 Einstein Street, Ness Ziona, 74140, Israel


  1. Barker RA, Mason SL, Harrower TP, Swain RA, Ho AK, Sahakian BJ, et al. The long-term safety and efficacy of bilateral transplantation of human fetal striatal tissue in patients with mild to moderate Huntington’s disease. J Neurol Neurosurg Psychiatry. 2013;84:657–65.PubMed CentralPubMedView ArticleGoogle Scholar
  2. Cisbani G, Cicchetti F. An in vitro perspective on the molecular mechanisms underlying mutant huntingtin protein toxicity. Cell Death Dis. 2012;3:e382.PubMed CentralPubMedView ArticleGoogle Scholar
  3. Maucksch C, Vazey EM, Gordon RJ, Connor B. Stem cell-based therapy for Huntington’s disease. J Cell Biochem. 2013;114:754–63.PubMedView ArticleGoogle Scholar
  4. Papp KV, Kaplan RF, Snyder PJ. Biological markers of cognition in prodromal Huntington’s disease: a review. Brain Cogn. 2011;77:280–91.PubMedView ArticleGoogle Scholar
  5. Petersen A, Larsen KE, Behr GG, Romero N, Przedborski S, Brundin P, et al. Expanded CAG repeats in exon 1 of the Huntington’s disease gene stimulate dopamine-mediated striatal neuron autophagy and degeneration. Hum Mol Genet. 2001;10:1243–54.PubMedView ArticleGoogle Scholar
  6. Klempir J, Zidovska J, Stochl J, Ing VK, Uhrova T, Roth J. The number of CAG repeats within the normal allele does not influence the age of onset in Huntington’s disease. Mov Disord. 2011;26:125–9.PubMedView ArticleGoogle Scholar
  7. Lee JM, Ramos EM, Lee JH, Gillis T, Mysore JS, Hayden MR, et al. CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion. Neurology. 2012;78:690–5.PubMed CentralPubMedView ArticleGoogle Scholar
  8. Rosenblatt A, Kumar BV, Mo A, Welsh CS, Margolis RL, Ross CA. Age, CAG repeat length, and clinical progression in Huntington’s disease. Mov Disord. 2012;27:272–6.PubMedView ArticleGoogle Scholar
  9. Harper PS. The epidemiology of Huntington’s disease. Hum Genet. 1992;89:365–76.PubMedView ArticleGoogle Scholar
  10. Walker FO. Huntington’s disease. Lancet. 2007;369:218–28.PubMedView ArticleGoogle Scholar
  11. Ha AD, Fung VS. Huntington’s disease. Curr Opin Neurol. 2012;25:491–8.PubMedView ArticleGoogle Scholar
  12. Ross CA, Tabrizi SJ. Huntington’s disease: from molecular pathogenesis to clinical treatment. Lancet Neurol. 2011;10:83–98.PubMedView ArticleGoogle Scholar
  13. Landles C, Bates GP. Huntingtin and the molecular pathogenesis of Huntington’s disease. Fourth in molecular medicine review series. EMBO Rep. 2004;5:958–63.PubMed CentralPubMedView ArticleGoogle Scholar
  14. Vonsattel JP, DiFiglia M. Huntington disease. J Neuropathol Exp Neurol. 1998;57:369–84.PubMedView ArticleGoogle Scholar
  15. Heinsen H, Rub U, Gangnus D, Jungkunz G, Bauer M, Ulmar G, et al. Nerve cell loss in the thalamic centromedian-parafascicular complex in patients with Huntington’s disease. Acta Neuropathol. 1996;91:161–8.PubMedView ArticleGoogle Scholar
  16. Kassubek J, Juengling FD, Kioschies T, Henkel K, Karitzky J, Kramer B, et al. Topography of cerebral atrophy in early Huntington’s disease: a voxel based morphometric MRI study. J Neurol Neurosurg Psychiatry. 2004;75:213–20.PubMed CentralPubMedGoogle Scholar
  17. Kremer HP, Roos RA, Dingjan G, Marani E, Bots GT. Atrophy of the hypothalamic lateral tuberal nucleus in Huntington’s disease. J Neuropathol Exp Neurol. 1990;49:371–82.PubMedView ArticleGoogle Scholar
  18. Petersen A, Gil J, Maat-Schieman ML, Bjorkqvist M, Tanila H, Araujo IM, et al. Orexin loss in Huntington’s disease. Hum Mol Genet. 2005;14:39–47.PubMedView ArticleGoogle Scholar
  19. Harper PS. Huntington Disease. In: eLS. Chichester: John Wiley & Sons Ltd; 2006.; doi:10.1038/npg.els.0005150.
  20. Paulsen JS, Langbehn DR, Stout JC, Aylward E, Ross CA, Nance M, et al. Detection of Huntington’s disease decades before diagnosis: the Predict-HD study. J Neurol Neurosurg Psychiatry. 2008;79:874–80.PubMed CentralPubMedView ArticleGoogle Scholar
  21. Lange H, Thorner G, Hopf A, Schroder KF. Morphometric studies of the neuropathological changes in choreatic diseases. J Neurol Sci. 1976;28:401–25.PubMedView ArticleGoogle Scholar
  22. Li SH, Li XJ. Huntingtin-protein interactions and the pathogenesis of Huntington’s disease. Trends Genet. 2004;20:146–54.PubMedView ArticleGoogle Scholar
  23. Sharp AH, Loev SJ, Schilling G, Li SH, Li XJ, Bao J, et al. Widespread expression of Huntington’s disease gene (IT15) protein product. Neuron. 1995;14:1065–74.PubMedView ArticleGoogle Scholar
  24. Trottier Y, Lutz Y, Stevanin G, Imbert G, Devys D, Cancel G, et al. Polyglutamine expansion as a pathological epitope in Huntington’s disease and four dominant cerebellar ataxias. Nature. 1995;378:403–6.PubMedView ArticleGoogle Scholar
  25. Walling HW, Baldassare JJ, Westfall TC. Molecular aspects of Huntington’s disease. J Neurosci Res. 1998;54:301–8.PubMedView ArticleGoogle Scholar
  26. Hunt VP, Walker FO. Dysphagia in Huntington’s disease. J Neurosci Nurs. 1989;21:92–5.PubMedView ArticleGoogle Scholar
  27. Kahlem P, Terre C, Green H, Djian P. Peptides containing glutamine repeats as substrates for transglutaminase-catalyzed cross-linking: relevance to diseases of the nervous system. Proc Natl Acad Sci U S A. 1996;93:14580–5.PubMed CentralPubMedView ArticleGoogle Scholar
  28. Bennett EJ, Shaler TA, Woodman B, Ryu KY, Zaitseva TS, Becker CH, et al. Global changes to the ubiquitin system in Huntington’s disease. Nature. 2007;448:704–8.PubMedView ArticleGoogle Scholar
  29. DiFiglia M, Sapp E, Chase KO, Davies SW, Bates GP, Vonsattel JP, et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science. 1997;277:1990–3.PubMedView ArticleGoogle Scholar
  30. Dragatsis I, Levine MS, Zeitlin S. Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice. Nat Genet. 2000;26:300–6.PubMedView ArticleGoogle Scholar
  31. Duyao MP, Auerbach AB, Ryan A, Persichetti F, Barnes GT, McNeil SM, et al. Inactivation of the mouse Huntington’s disease gene homolog Hdh. Science. 1995;269:407–10.PubMedView ArticleGoogle Scholar
  32. Leavitt BR, Guttman JA, Hodgson JG, Kimel GH, Singaraja R, Vogl AW, et al. Wild-type huntingtin reduces the cellular toxicity of mutant huntingtin in vivo. Am J Hum Genet. 2001;68:313–24.PubMed CentralPubMedView ArticleGoogle Scholar
  33. Nasir J, Floresco SB, O’Kusky JR, Diewert VM, Richman JM, Zeisler J, et al. Targeted disruption of the Huntington’s disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell. 1995;81:811–23.PubMedView ArticleGoogle Scholar
  34. Zeitlin S, Liu JP, Chapman DL, Papaioannou VE, Efstratiadis A. Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington’s disease gene homologue. Nat Genet. 1995;11:155–63.PubMedView ArticleGoogle Scholar
  35. Martindale D, Hackam A, Wieczorek A, Ellerby L, Wellington C, McCutcheon K, et al. Length of huntingtin and its polyglutamine tract influences localization and frequency of intracellular aggregates. Nat Genet. 1998;18:150–4.PubMedView ArticleGoogle Scholar
  36. Kazantsev A, Preisinger E, Dranovsky A, Goldgaber D, Housman D. Insoluble detergent-resistant aggregates form between pathological and nonpathological lengths of polyglutamine in mammalian cells. Proc Natl Acad Sci U S A. 1999;96:11404–9.PubMed CentralPubMedView ArticleGoogle Scholar
  37. Trushina E, Dyer RB, Badger 2nd JD, Ure D, Eide L, Tran DD, et al. Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro. Mol Cell Biol. 2004;24:8195–209.PubMed CentralPubMedView ArticleGoogle Scholar
  38. Cicchetti F, Lacroix S, Cisbani G, Vallieres N, Saint-Pierre M, St-Amour I, et al. Mutant huntingtin is present in neuronal grafts in Huntington disease patients. Ann Neurol. 2014;76:31–42.PubMedView ArticleGoogle Scholar
  39. Tan Z, Dai W, van Erp TG, Overman J, Demuro A, Digman MA, et al. Huntington’s disease cerebrospinal fluid seeds aggregation of mutant huntingtin. Mol Psychiatry. 2015. doi:10.1038/mp.2015.81.Google Scholar
  40. Baquet ZC, Gorski JA, Jones KR. Early striatal dendrite deficits followed by neuron loss with advanced age in the absence of anterograde cortical brain-derived neurotrophic factor. J Neurosci. 2004;24:4250–8.PubMedView ArticleGoogle Scholar
  41. Ivkovic S, Ehrlich ME. Expression of the striatal DARPP-32/ARPP-21 phenotype in GABAergic neurons requires neurotrophins in vivo and in vitro. J Neurosci. 1999;19:5409–19.PubMedGoogle Scholar
  42. Ventimiglia R, Mather PE, Jones BE, Lindsay RM. The neurotrophins BDNF, NT-3 and NT-4/5 promote survival and morphological and biochemical differentiation of striatal neurons in vitro. Eur J Neurosci. 1995;7:213–22.PubMedView ArticleGoogle Scholar
  43. Xie Y, Hayden MR, Xu B. BDNF overexpression in the forebrain rescues Huntington’s disease phenotypes in YAC128 mice. J Neurosci. 2010;30:14708–18.PubMed CentralPubMedView ArticleGoogle Scholar
  44. Zuccato C, Marullo M, Vitali B, Tarditi A, Mariotti C, Valenza M, et al. Brain-derived neurotrophic factor in patients with Huntington’s disease. PLoS One. 2011;6:e22966.PubMed CentralPubMedView ArticleGoogle Scholar
  45. Barzilay R, Ben-Zur T, Sadan O, Bren Z, Taler M, Lev N, et al. Intracerebral adult stem cells transplantation increases brain-derived neurotrophic factor levels and protects against phencyclidine-induced social deficit in mice. Transl Psychiatry. 2011;1:e61.PubMed CentralPubMedView ArticleGoogle Scholar
  46. Marconi S, Castiglione G, Turano E, Bissolotti G, Angiari S, Farinazzo A, et al. Human adipose-derived mesenchymal stem cells systemically injected promote peripheral nerve regeneration in the mouse model of sciatic crush. Tissue Eng. 2012;18:1264–72.View ArticleGoogle Scholar
  47. Wilkins A, Kemp K, Ginty M, Hares K, Mallam E, Scolding N. Human bone marrow-derived mesenchymal stem cells secrete brain-derived neurotrophic factor which promotes neuronal survival in vitro. Stem Cell Res. 2009;3:63–70.PubMedView ArticleGoogle Scholar
  48. Zuccato C, Liber D, Ramos C, Tarditi A, Rigamonti D, Tartari M, et al. Progressive loss of BDNF in a mouse model of Huntington’s disease and rescue by BDNF delivery. Pharmacol Res. 2005;52:133–9.PubMedView ArticleGoogle Scholar
  49. Scheuing L, Chiu CT, Liao HM, Linares GR, Chuang DM. Preclinical and clinical investigations of mood stabilizers for Huntington’s disease: what have we learned? Int J Biol Sci. 2014;10:1024–38.PubMed CentralPubMedView ArticleGoogle Scholar
  50. Crigler L, Robey RC, Asawachaicharn A, Gaupp D, Phinney DG. Human mesenchymal stem cell subpopulations express a variety of neuro-regulatory molecules and promote neuronal cell survival and neuritogenesis. Exp Neurol. 2006;198:54–64.PubMedView ArticleGoogle Scholar
  51. Ellrichmann G, Reick C, Saft C, Linker RA. The role of the immune system in Huntington’s disease. Clin Dev Immunol. 2013;2013:541259.PubMed CentralPubMedView ArticleGoogle Scholar
  52. Soulet D, Cicchetti F. The role of immunity in Huntington’s disease. Mol Psychiatry. 2011;16:889–902.PubMedView ArticleGoogle Scholar
  53. Dalrymple A, Wild EJ, Joubert R, Sathasivam K, Bjorkqvist M, Petersen A, et al. Proteomic profiling of plasma in Huntington’s disease reveals neuroinflammatory activation and biomarker candidates. J Proteome Res. 2007;6:2833–40.PubMedView ArticleGoogle Scholar
  54. Trager U, Magnusson A, Lahiri Swales N, Wild E, North J, Lowdell M, et al. JAK/STAT signalling in Huntington's disease immune cells. PLoS Curr. 2013;5. doi:10.1371/currents.hd.5791c897b5c3bebeed93b1d1da0c0648
  55. Weiss A, Trager U, Wild EJ, Grueninger S, Farmer R, Landles C, et al. Mutant huntingtin fragmentation in immune cells tracks Huntington’s disease progression. J Clin Invest. 2012;122:3731–6.PubMed CentralPubMedView ArticleGoogle Scholar
  56. Bjorkqvist M, Wild EJ, Thiele J, Silvestroni A, Andre R, Lahiri N, et al. A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington’s disease. J Exp Med. 2008;205:1869–77.PubMed CentralPubMedView ArticleGoogle Scholar
  57. Wild E, Bjorkqvist M, Tabrizi SJ. Immune markers for Huntington’s disease? Expert Rev Neurother. 2008;8:1779–81.PubMedView ArticleGoogle Scholar
  58. Trager U, Andre R, Magnusson-Lind A, Miller JR, Connolly C, Weiss A, et al. Characterisation of immune cell function in fragment and full-length Huntington’s disease mouse models. Neurobiol Dis. 2014;73C:388–98.Google Scholar
  59. Mastrokolias A, Ariyurek Y, Goeman JJ, van Duijn E, Roos RA, van der Mast RC, et al. Huntington’s disease biomarker progression profile identified by transcriptome sequencing in peripheral blood. Eur J Hum Genet. 2015;23:1349–56.PubMed CentralPubMedView ArticleGoogle Scholar
  60. Bruner DW, Movsas B, Basch E. Capturing the patient perspective: patient-reported outcomes as clinical trial endpoints. Am Soc Clin Oncol Educ Book. 2012:139–44Google Scholar
  61. Bantubungi K, Blum D, Cuvelier L, Wislet-Gendebien S, Rogister B, Brouillet E, et al. Stem cell factor and mesenchymal and neural stem cell transplantation in a rat model of Huntington’s disease. Mol Cell Neurosci. 2008;37:454–70.PubMedView ArticleGoogle Scholar
  62. Johann V, Schiefer J, Sass C, Mey J, Brook G, Kruttgen A, et al. Time of transplantation and cell preparation determine neural stem cell survival in a mouse model of Huntington’s disease. Exp Brain Res. 2007;177:458–70.PubMedView ArticleGoogle Scholar
  63. Lee ST, Chu K, Park JE, Lee K, Kang L, Kim SU, et al. Intravenous administration of human neural stem cells induces functional recovery in Huntington’s disease rat model. Neurosci Res. 2005;52:243–9.PubMedView ArticleGoogle Scholar
  64. Lee ST, Park JE, Lee K, Kang L, Chu K, Kim SU, et al. Noninvasive method of immortalized neural stem-like cell transplantation in an experimental model of Huntington’s disease. J Neurosci Methods. 2006;152:250–4.PubMedView ArticleGoogle Scholar
  65. McBride JL, Behrstock SP, Chen EY, Jakel RJ, Siegel I, Svendsen CN, et al. Human neural stem cell transplants improve motor function in a rat model of Huntington’s disease. J Comp Neurol. 2004;475:211–9.PubMedView ArticleGoogle Scholar
  66. Vazey EM, Chen K, Hughes SM, Connor B. Transplanted adult neural progenitor cells survive, differentiate and reduce motor function impairment in a rodent model of Huntington’s disease. Exp Neurol. 2006;199:384–96.PubMedView ArticleGoogle Scholar
  67. Vazey EM, Dottori M, Jamshidi P, Tomas D, Pera MF, Horne M, et al. Comparison of transplant efficiency between spontaneously derived and noggin-primed human embryonic stem cell neural precursors in the quinolinic acid rat model of Huntington’s disease. Cell Transplant. 2010;19:1055–62.PubMedView ArticleGoogle Scholar
  68. Roberts TJ, Price J, Williams SC, Modo M. Preservation of striatal tissue and behavioral function after neural stem cell transplantation in a rat model of Huntington’s disease. Neuroscience. 2006;139:1187–99.PubMedView ArticleGoogle Scholar
  69. Ryu JK, Kim J, Cho SJ, Hatori K, Nagai A, Choi HB, et al. Proactive transplantation of human neural stem cells prevents degeneration of striatal neurons in a rat model of Huntington disease. Neurobiol Dis. 2004;16:68–77.PubMedView ArticleGoogle Scholar
  70. Guillemin GJ. Quinolinic acid, the inescapable neurotoxin. FEBS J. 2012;279:1356–65.PubMedView ArticleGoogle Scholar
  71. Dong XX, Wang Y, Qin ZH. Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Acta Pharmacol Sinica. 2009;30:379–87.View ArticleGoogle Scholar
  72. Mangiarini L, Sathasivam K, Seller M, Cozens B, Harper A, Hetherington C, et al. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell. 1996;87:493–506.PubMedView ArticleGoogle Scholar
  73. Beal MF, Ferrante RJ. Experimental therapeutics in transgenic mouse models of Huntington’s disease. Nat Rev Neurosci. 2004;5:373–84.PubMedView ArticleGoogle Scholar
  74. Schilling G, Becher MW, Sharp AH, Jinnah HA, Duan K, Kotzuk JA, et al. Intranuclear inclusions and neuritic aggregates in transgenic mice expressing a mutant N-terminal fragment of huntingtin. Hum Mol Genet. 1999;8:397–407.PubMedView ArticleGoogle Scholar
  75. Ramaswamy S, McBride JL, Kordower JH. Animal models of Huntington’s disease. Ilar J. 2007;48:356–73.PubMedView ArticleGoogle Scholar
  76. Klassen H, Imfeld KL, Ray J, Young MJ, Gage FH, Berman MA. The immunological properties of adult hippocampal progenitor cells. Vision Res. 2003;43:947–56.PubMedView ArticleGoogle Scholar
  77. Richardson RM, Broaddus WC, Holloway KL, Sun D, Bullock MR, Fillmore HL. Heterotypic neuronal differentiation of adult subependymal zone neuronal progenitor cells transplanted to the adult hippocampus. Mol Cell Neurosci. 2005;28:674–82.PubMedView ArticleGoogle Scholar
  78. Zhang RL, Zhang L, Zhang ZG, Morris D, Jiang Q, Wang L, et al. Migration and differentiation of adult rat subventricular zone progenitor cells transplanted into the adult rat striatum. Neuroscience. 2003;116:373–82.PubMedView ArticleGoogle Scholar
  79. Kokaia Z, Martino G, Schwartz M, Lindvall O. Cross-talk between neural stem cells and immune cells: the key to better brain repair? Nat Neurosci. 2012;15:1078–87.PubMedView ArticleGoogle Scholar
  80. Einstein O, Ben-Hur T. The changing face of neural stem cell therapy in neurologic diseases. Arch Neurol. 2008;65:452–6.PubMedView ArticleGoogle Scholar
  81. Fainstein N, Vaknin I, Einstein O, Zisman P, Ben Sasson SZ, Baniyash M, et al. Neural precursor cells inhibit multiple inflammatory signals. Mol Cell Neurosci. 2008;39:335–41.PubMedView ArticleGoogle Scholar
  82. Kordower JH, Rosenstein JM, Collier TJ, Burke MA, Chen EY, Li JM, et al. Functional fetal nigral grafts in a patient with Parkinson’s disease: chemoanatomic, ultrastructural, and metabolic studies. J Comp Neurol. 1996;370:203–30.PubMedView ArticleGoogle Scholar
  83. Gomi M, Aoki T, Takagi Y, Nishimura M, Ohsugi Y, Mihara M, et al. Single and local blockade of interleukin-6 signaling promotes neuronal differentiation from transplanted embryonic stem cell-derived neural precursor cells. J Neurosci Res. 2011;89:1388–99.PubMedView ArticleGoogle Scholar
  84. Subramanian T, Pollack IF, Lund RD. Rejection of mesencephalic retinal xenografts in the rat induced by systemic administration of recombinant interferon-gamma. Exp Neurol. 1995;131:157–62.PubMedView ArticleGoogle Scholar
  85. Reekmans KP, Praet J, De Vocht N, Tambuyzer BR, Bergwerf I, Daans J, et al. Clinical potential of intravenous neural stem cell delivery for treatment of neuroinflammatory disease in mice? Cell Transplant. 2011;20:851–69.PubMedView ArticleGoogle Scholar
  86. Caplan AI, Lanza R, Gearhart J, Hogan B, Melton D, Pedersen R, et al. Mesenchymal stem cells. In: Atala A, Lanza R, editors. Handbook of stem cells. Burlington: Academic; 2004. p. 299–308.View ArticleGoogle Scholar
  87. Kerkis I, Ambrosio CE, Kerkis A, Martins DS, Zucconi E, Fonseca SA, et al. Early transplantation of human immature dental pulp stem cells from baby teeth to golden retriever muscular dystrophy (GRMD) dogs: Local or systemic? J Transl Med. 2008;6:35.PubMed CentralPubMedView ArticleGoogle Scholar
  88. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284:143–7.PubMedView ArticleGoogle Scholar
  89. Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006;98:1076–84.PubMedView ArticleGoogle Scholar
  90. Bianco P, Cao X, Frenette PS, Mao JJ, Robey PG, Simmons PJ, et al. The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat Med. 2013;19:35–42.PubMed CentralPubMedView ArticleGoogle Scholar
  91. Caplan AI, Correa D. The MSC: an injury drugstore. Cell Stem Cell. 2011;9:11–5.PubMed CentralPubMedView ArticleGoogle Scholar
  92. Singer NG, Caplan AI. Mesenchymal stem cells: mechanisms of inflammation. Annu Rev Pathol. 2014;6:457–78.View ArticleGoogle Scholar
  93. Caplan AI. Adult mesenchymal stem cells and women’s health. Menopause. 2015;22:131–5.PubMedView ArticleGoogle Scholar
  94. Murphy MB, Moncivais K, Caplan AI. Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine. Exp Mol Med. 2013;45:e54.PubMed CentralPubMedView ArticleGoogle Scholar
  95. Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8:315–7.PubMedView ArticleGoogle Scholar
  96. Snyder BR, Chiu AM, Prockop DJ, Chan AW. Human multipotent stromal cells (MSCs) increase neurogenesis and decrease atrophy of the striatum in a transgenic mouse model for Huntington’s disease. PLoS One. 2010;5:e9347.PubMed CentralPubMedView ArticleGoogle Scholar
  97. Augello A, Tasso R, Negrini SM, Amateis A, Indiveri F, Cancedda R, et al. Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway. Eur J Immunol. 2005;35:1482–90.PubMedView ArticleGoogle Scholar
  98. Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation. 2003;75:389–97.PubMedView ArticleGoogle Scholar
  99. Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringden O. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol. 2003;31:890–6.PubMedView ArticleGoogle Scholar
  100. De Miguel MP, Fuentes-Julian S, Blazquez-Martinez A, Pascual CY, Aller MA, Arias J, et al. Immunosuppressive properties of mesenchymal stem cells: advances and applications. Curr Mol Med. 2012;12:574–91.PubMedView ArticleGoogle Scholar
  101. Yoo SW, Chang DY, Lee HS, Kim GH, Park JS, Ryu BY, et al. Immune following suppression mesenchymal stem cell transplantation in the ischemic brain is mediated by TGF-beta. Neurobiol Dis. 2013;58:249–57.PubMedView ArticleGoogle Scholar
  102. Zhang R, Liu Y, Yan K, Chen L, Chen XR, Li P, et al. Anti-inflammatory and immunomodulatory mechanisms of mesenchymal stem cell transplantation in experimental traumatic brain injury. J Neuroinflammation. 2013;10:106.PubMed CentralPubMedView ArticleGoogle Scholar
  103. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005;105:1815–22.PubMedView ArticleGoogle Scholar
  104. Ankrum JA, Ong JF, Karp JM. Mesenchymal stem cells: immune evasive, not immune privileged. Nat Biotechnol. 2014;32:252–60.PubMed CentralPubMedView ArticleGoogle Scholar
  105. English K. Mechanisms of mesenchymal stromal cell immunomodulation. Immunol Cell Biol. 2013;91:19–26.PubMedView ArticleGoogle Scholar
  106. Griffin MD, Ryan AE, Alagesan S, Lohan P, Treacy O, Ritter T. Anti-donor immune responses elicited by allogeneic mesenchymal stem cells: what have we learned so far? Immunol Cell Biol. 2013;91:40–51.PubMedView ArticleGoogle Scholar
  107. Le Blanc K, Ringden O. Mesenchymal stem cells: properties and role in clinical bone marrow transplantation. Curr Opin Immunol. 2006;18:586–91.PubMedView ArticleGoogle Scholar
  108. Danielyan L, Schafer R, von Ameln-Mayerhofer A, Buadze M, Geisler J, Klopfer T, et al. Intranasal delivery of cells to the brain. Eur J Cell Biol. 2009;88:315–24.PubMedView ArticleGoogle Scholar
  109. Joyce N, Annett G, Wirthlin L, Olson S, Bauer G, Nolta JA. Mesenchymal stem cells for the treatment of neurodegenerative disease. Regen Med. 2010;5:933–46.PubMed CentralPubMedView ArticleGoogle Scholar
  110. Liu L, Eckert MA, Riazifar H, Kang DK, Agalliu D, Zhao W. From blood to the brain: can systemically transplanted mesenchymal stem cells cross the blood-brain barrier? Stem Cells Int. 2013;2013:435093.PubMed CentralPubMedGoogle Scholar
  111. Messina C, Faraci M, de Fazio V, Dini G, Calo MP, Calore E. Prevention and treatment of acute GvHD. Bone Marrow Transplant. 2008;41 Suppl 2:S65–70.PubMedView ArticleGoogle Scholar
  112. Chen SL, Fang WW, Qian J, Ye F, Liu YH, Shan SJ, et al. Improvement of cardiac function after transplantation of autologous bone marrow mesenchymal stem cells in patients with acute myocardial infarction. Chinese Med J. 2004;117:1443–8.Google Scholar
  113. Hare JM, Traverse JH, Henry TD, Dib N, Strumpf RK, Schulman SP, et al. A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am College Cardiol. 2009;54:2277–86.View ArticleGoogle Scholar
  114. Kharaziha P, Hellstrom PM, Noorinayer B, Farzaneh F, Aghajani K, Jafari F, et al. Improvement of liver function in liver cirrhosis patients after autologous mesenchymal stem cell injection: a phase I-II clinical trial. Eur J Gastroenterol Hepatol. 2009;21:1199–205.PubMedView ArticleGoogle Scholar
  115. ClinicalTrials Bethesda2015 Cited 26 June 2015.
  116. Engelhardt B, Sorokin L. The blood-brain and the blood-cerebrospinal fluid barriers: function and dysfunction. Semin Immunopathol. 2009;31:497–511.PubMedView ArticleGoogle Scholar
  117. Owens T, Bechmann I, Engelhardt B. Perivascular spaces and the two steps to neuroinflammation. J Neuropathol Exp Neurol. 2008;67:1113–21.PubMedView ArticleGoogle Scholar
  118. Honmou O, Onodera R, Sasaki M, Waxman SG, Kocsis JD. Mesenchymal stem cells: therapeutic outlook for stroke. Trends Mol Med. 2012;18:292–7.PubMedView ArticleGoogle Scholar
  119. Jeon D, Chu K, Lee ST, Jung KH, Kang KM, Ban JJ, et al. A cell-free extract from human adipose stem cells protects mice against epilepsy. Epilepsia. 2011;52:1617–26.PubMedView ArticleGoogle Scholar
  120. Kim S, Chang KA, Kim J, Park HG, Ra JC, Kim HS, et al. The preventive and therapeutic effects of intravenous human adipose-derived stem cells in Alzheimer’s disease mice. PLoS One. 2012;7:e45757.PubMed CentralPubMedView ArticleGoogle Scholar
  121. Matsushita T, Kibayashi T, Katayama T, Yamashita Y, Suzuki S, Kawamata J, et al. Mesenchymal stem cells transmigrate across brain microvascular endothelial cell monolayers through transiently formed inter-endothelial gaps. Neurosci Lett. 2011;502:41–5.PubMedView ArticleGoogle Scholar
  122. Fink KD, Rossignol J, Crane AT, Davis KK, Bombard MC, Bavar AM, et al. Transplantation of umbilical cord-derived mesenchymal stem cells into the striata of R6/2 mice: behavioral and neuropathological analysis. Stem Cell Res Ther. 2013;4:130.PubMed CentralPubMedView ArticleGoogle Scholar
  123. Lee ST, Chu K, Jung KH, Im WS, Park JE, Lim HC, et al. Slowed progression in models of Huntington disease by adipose stem cell transplantation. Ann Neurol. 2009;66:671–81.PubMedView ArticleGoogle Scholar
  124. Lin YT, Chern Y, Shen CK, Wen HL, Chang YC, Li H, et al. Human mesenchymal stem cells prolong survival and ameliorate motor deficit through trophic support in Huntington’s disease mouse models. PLoS One. 2011;6:e22924.PubMed CentralPubMedView ArticleGoogle Scholar
  125. Moraes L, Vasconcelos-dos-Santos A, Santana FC, Godoy MA, Rosado-de-Castro PH, Jasmin, et al. Neuroprotective effects and magnetic resonance imaging of mesenchymal stem cells labeled with SPION in a rat model of Huntington’s disease. Stem Cell Res. 2012;9:143–55.PubMedView ArticleGoogle Scholar
  126. Rossignol J, Boyer C, Leveque X, Fink KD, Thinard R, Blanchard F, et al. Mesenchymal stem cell transplantation and DMEM administration in a 3NP rat model of Huntington’s disease: morphological and behavioral outcomes. Behav Brain Res. 2011;217:369–78.PubMedView ArticleGoogle Scholar
  127. Koellensperger E, Lampe K, Beierfuss A, Gramley F, Germann G, Leimer U. Intracutaneously injected human adipose tissue-derived stem cells in a mouse model stay at the site of injection. J Plast Reconstr Aesthet Surg. 2014;67:844–50.PubMedView ArticleGoogle Scholar
  128. Dore-Duffy P, Katychev A, Wang X, Van Buren E. CNS microvascular pericytes exhibit multipotential stem cell activity. J Cereb Blood Flow Metab. 2006;26:613–24.PubMedView ArticleGoogle Scholar
  129. Mullen RJ, Buck CR, Smith AM. NeuN, a neuronal specific nuclear protein in vertebrates. Development. 1992;116:201–11.PubMedGoogle Scholar
  130. Sanberg PR, Pisa M, Fibiger HC. Kainic acid injections in the striatum alter the cataleptic and locomotor effects of drugs influencing dopaminergic and cholinergic systems. Eur J Pharmacol. 1981;74:347–57.PubMedView ArticleGoogle Scholar
  131. Bachoud-Levi AC, Gaura V, Brugieres P, Lefaucheur JP, Boisse MF, Maison P, et al. Effect of fetal neural transplants in patients with Huntington’s disease 6 years after surgery: a long-term follow-up study. Lancet Neurol. 2006;5:303–9.PubMedView ArticleGoogle Scholar
  132. Yang CR, Yu RK. Intracerebral transplantation of neural stem cells combined with trehalose ingestion alleviates pathology in a mouse model of Huntington’s disease. J Neurosci Res. 2009;87:26–33.PubMed CentralPubMedView ArticleGoogle Scholar
  133. Reyes S, Tajiri N, Borlongan CV. Developments in intracerebral stem cell grafts. Expert Rev Neurother. 2015;15:381–93.PubMedView ArticleGoogle Scholar
  134. Lee J-M, Wheeler VC, Chao MJ, Vonsattel JPG, Pinto RM, Lucente D, et al. Identification of genetic factors that modify clinical onset of Huntington’s disease. Cell. 2015;162:516–26.View ArticleGoogle Scholar
  135. Wild EJ, Boggio R, Langbehn D, Robertson N, Haider S, Miller JRC, et al. Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington’s disease patients. J Clin Invest. 2015;125:1979–86.PubMed CentralPubMedView ArticleGoogle Scholar
  136. Tai YF, Pavese N, Gerhard A, Tabrizi SJ, Barker RA, Brooks DJ, et al. Microglial activation in presymptomatic Huntington’s disease gene carriers. Brain. 2007;130:1759–66.PubMedView ArticleGoogle Scholar
  137. Chen J, Lin M, Foxe JJ, Pedrosa E, Hrabovsky A, Carroll R, et al. Transcriptome comparison of human neurons generated using induced pluripotent stem cells derived from dental pulp and skin fibroblasts. PLoS One. 2013;8:e75682.PubMed CentralPubMedView ArticleGoogle Scholar


© Kerkis et al. 2015