Skip to main content
Download PDF

Adipose tissue-derived stromal vascular fraction in regenerative medicine: a brief review on biology and translation

Stem Cell Research & Therapy volume 8, Article number: 145 (2017) Cite this article

Abstract

Adipose/fat tissue provides an abundant source of stromal vascular fraction (SVF) cells for immediate administration and can also give rise to a substantial number of cultured, multipotent adipose-derived stromal cells (ADSCs). Recently, both SVF and ADSCs have gained wide-ranging translational significance in regenerative medicine. Initially used for cosmetic breast enhancement, this mode of treatment has found use in many diseases involving immune disorders, tissue degeneration, and ischaemic conditions. In this review, we try to address several important aspects of this field, outlining the biology, technology, translation, and challenges related to SVF- and ADSC-based therapies. Starting from the basics of SVF and ADSC isolation, we touch upon recently developed technologies, addressing elements of novel methods and devices under development for point-of-care isolation of SVF. Characterisation of SVF cells and ADSCs is also an evolving area and we look into unusual expression of CD34 antigen as an interesting marker for such purposes. Based on reports involving different cells of the SVF, we draw a potential mode of action, focussing on angiogenesis since it involves multiple cells, unlike immunomodulation which is governed predominantly by ADSCs. We have looked into the latest research, experimental therapies, and clinical trials which are utilising SVF/ADSCs in conditions such as multiple sclerosis, Crohn’s disease, peripheral neuropathy, osteoarthritis, diabetic foot ulcer, and so forth. However, problems have arisen with regards to the lack of proper regulatory guidelines for such therapies and, since the introduction of US Food and Drug Administration draft guidelines and the Reliable and Effective Growth for Regenerative Health Options that Improve Wellness (REGROW) Act, the debate became more public with regards to safe and efficacious use of these cells.

Background

Adipose-derived stem/stromal cells (ADSCs) were first characterised in 2001, and have since been widely studied and used as a major source of cells with regenerative potential, with characteristics similar to that of mesenchymal stem/stromal cells (MSCs) [1,2,3,4]. ADSCs are isolated as part of the aqueous fraction derived from enzymatic digestion of lipoaspirate (the product of liposuction). This aqueous fraction, a combination of ADSCs, endothelial precursor cells (EPCs), endothelial cells (ECs), macrophages, smooth muscle cells, lymphocytes, pericytes, and pre-adipocytes among others, is what is known as the stromal vascular fraction (SVF).

ADSCs, like MSCs, have shown promise in regenerative and reconstructive medicine [5,6,7,8]. Recent advances in the area of tissue regeneration have put SVF on a par and at times even above ADSCs [9,10,11,12,13,14,15,16,17]. For instance, in a study of erectile function in a rat model of cavernous nerve injury, SVF treatment showed superior statistically significant results compared to ADSC treatment alone, especially in smooth muscle/collagen ratio and in endothelial cell content [12]. The advantage of SVF over ADSCs is believed to be in two fundamental areas. Firstly, although similar in properties such as immunomodulation, anti-inflammatory, angiogenesis, and so forth, the distinctive, heterogeneous cellular composition of SVF may be responsible for the better therapeutic outcome observed in comparative animal studies [9,10,11,12]. Secondly, unlike ADSCs, SVF is much more easily acquired, without the need for any cell separation or culturing conditions. Thus, the therapeutic cellular product is instantaneously obtained and has minimal contact with reagents making it comparatively safer and subject to the fulfilment of lesser regulatory criteria. It should be noted that, whereas ADSCs find utility in both allogeneic and autologous treatments, SVF, owing to the presence of various cell types known to cause immunological rejection, is suitable for autologous treatments only.

Although almost all ADSCs are derived from the white adipose tissue (WAT), as covered in this review, the identification of progenitor cells in brown adipose tissue (BAT) of adult humans is fascinating and worth a mention [18, 19]. Termed as BADSCs (brown adipose-derived stem cells), these have been isolated from BAT deposits present in relatively inaccessible regions such as the mediastinum, and are capable of differentiating to metabolically active BA cells with differences in surface antigen expression as compared to WAT-originating ADSCs [18]. Current understanding of WAT and BAT define these cells with distinct functionalities, and thus translational avenues for ADSCs from either source should be compared to identify specific therapeutic targets and potential advantage of one over the other. Understanding of the molecular mechanisms behind either cell fate and the possibility of inter-conversion are interesting avenues of research with basic and translational implications [20, 21].

Despite the potential of SVF in regenerative medicine there are challenges to overcome. First is isolation of SVF, which needs a specialised infrastructure such as a clean room facility, equipment, reagents, and technical capabilities. These conditions limit the reach of SVF to only major hospitals in tier 1/2 cities, especially in a country such as India. In this regard, the up and coming point-of-care biomedical devices which can take lipoaspirate as their input and produce sterile, injectable SVF as output will be beneficial. Secondly, the method of isolating SVF is a vital roadblock in the approved use of SVF for therapeutic applications. Digestion of lipoaspirate is achieved by collagenase, and the presence of collagenase in the injectable product does not bode well with regulatory authorities such as the US Food and Drug Administration (FDA) [3]. Consequently, alternative methods are being explored with some encouraging outcomes [22,23,24,25]. Finally, characterisation of the regenerative cells of SVF has not reached a wide consensus. Organisations such as the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society of Cellular Therapy (ISCT) have been updating the surface antigen-based definition of SVF cells, where CD34 antigen, primarily associated with haematopoietic stem cells (HSCs), became an important marker of regenerative, MSC-like cells of the SVF [1, 26, 27].

In this review, using the broader topics of isolation and characterisation of SVF, we will touch upon some of the challenges and innovations in the field and comment upon the future of SVF.

Isolation of SVF

Enzymatic isolation of SVF

The most widely used technique for the isolation of SVF from lipoaspirate is by digestion of the fatty portion of the lipoaspirate with collagenase, separating the contents into two distinct phases: the floating mature adipocytes fraction, and the cellular components of interest in the lower aqueous fraction [17, 28]. This separation can be enhanced by centrifugation; nevertheless, comparable separation can be achieved by gravity-based phase separation and filtration [29]. Although centrifugation is more efficient, it will also pellet down all the cells present, while filtration can be designed to capture only the important cell types based on size, thus enriching the specific cellular cocktail.

Centrifugation of the aqueous fraction yields a reddish pellet which contains SVF cells. Erythrocytes, a major contaminant present in the SVF pellet, can be lysed to isolate a purer population of ADSCs and/or SVF cells if intended for in vitro expansion [7, 30].

Non-enzymatic isolation of SVF

In view of the regulatory questions relating to enzymatic isolation, it is important to look into alternative methods for isolating SVF and compare these with the conventional methods [3, 24, 25]. Most of these techniques involve mechanical agitation which breaks down the adipose tissue and releases the stromal cells. As expected, the cellular yield from mechanical procedures are much lower compared to enzymatic methods, as cells of the adipose tissue tightly bound by collagen will not be easily released by mechanical action alone [24].

A novel method of mechanical agitation was recently defined by Tonnard et al. [23]. The injectable product, termed as “nanofat”, was obtained by emulsification and filtration of the lipoaspirate. Although termed as nanofat grafting, in effect no viable adipose cells survived the emulsification process, but the graft was rich in CD34+ ADSCs. The efficacy and properties of nanofat have been demonstrated in multiple case studies related to skin rejuvenation, scar healing, skin grafting for wound management, and treating vulvar lichen sclerosus (VLS), a chronic inflammatory disease of the anogenital area, and also by standard ADSC-related phenotypic and differentiation studies [23, 31, 32]. Owing to the simplicity of the technique, it might be amenable to scaling up by simply using the desired volume of syringe and/or using multiple syringes as required.

The effect of the emulsification process on other cells of interest, normally found in enzymatically processed SVF, remains to be seen. Combining such techniques with centrifugation or filtration can yield products highly concentrated with ADSCs, thus eliminating enzymatic digestion, reducing process time, cost, and respective regulatory constraints.

Automated devices for point-of-care isolation of SVF

The infrastructure, expertise, and consumables required for the conventional method of SVF isolation is not commonplace in most health-care facilities. Cosmetic surgery, being at the upper-end of medical expenditure, is the largest consumer of SVF and related products, but the actual scope is much wider [3]. Thus, it is unfortunate that the benefits of this very simple technology have not reached full potential. This gap can be overcome by automated, point-of-care biomedical devices, which can produce injectable SVF from lipoaspirate.

Such developments have been underway for quite some time, although mostly still in trial stages, with Cytori’s (San Diego, USA) Celution® being the first system [33]. Currently, about 30 different automated and semi-automated systems are under development [22]. The technologies and methodologies used vary, with most opting for the tried and tested enzymatic process. Stempeutics (Bangalore, India) has developed one such system, Stempeutron™, the proof-of-concept of which was reported in SundarRaj et al. [29]. Stempeutron™ uses the more efficient and conventional enzymatic digestion method and gravity-enabled separation of fatty and aqueous fraction followed by filtration of the aqueous fraction to achieve SVF isolation and concentration.

Since Stempeutron™ uses filtration we wanted to know the physical dimensions of SVF cells. As such, a list of cell sizes was not found while searching through the literature for this review and we resorted to mining for individual reports of cell size, surface area, and volume measurements. Table 1 summarises available cell diameter information accumulated from various reports [34,35,36,37,38,39,40,41,42,43,44,45]. The filtration system in Stempeutron™ is capable of capturing the majority of the therapeutically important cell types (Table 1) [3, 29]. Future developments might enable size-based enrichment of specific cellular populations, targeted towards specific diseases.

Table 1 Important components of SVF, respective sizes, and surface markers
Full size table

Characterisation of SVF

Criteria for characterising the cellular contents of SVF using surface antigen (cluster of differentiation (CD)) combinations is an evolving area of research as, within certain generally accepted norms, it differs between laboratories. A list of commonly used positive and negative markers identifying different cellular populations of SVF is provided in Table 1 [1, 26, 29]. Considering the variables present in isolation of SVF, such as the age of the patient, downstream processing, and so forth, the diversity observed between samples is quite understandable. However, if there is a relationship between the different ratios of cellular components present in SVF with its efficacy towards specific ailments, one might be able to come up with an optimum composition corresponding to the highest therapeutic efficacy. Traktuev et al. demonstrated that certain factors produced by ADSCs such as vascular endothelial growth factor (VEGF) help in migration, and that better survival of EPCs and correspondingly platelet-derived growth factors (PDGF)-BB produced by EPCs enable ADSCs to proliferate and migrate [46, 47]. They also provide proof of physical interaction between ADSCs and ECs in which ECs form a stable tubular, vasculature-like structure with support from ADSCs, both in vitro and in vivo [47]. This information along with some other articles has been used to draw up a schematic in Fig. 1 for the action of SVF, focussing on the interaction between ADSCs and EPCs [46,47,48,49].

Fig. 1
figure 1

Potential mechanism of action of ADSCs and ECs present in SVF towards angiogenesis. Breakdown of adipose tissue releases many cell types, which together are termed SVF. The cells of the SVF can produce several bioactive soluble factors. ADSCs and EPCs, two important components of SVF, cross-talk via VEGF and PDGF-BB, respectively (among other components), to enable cell proliferation, homing towards injury, neovascularisation and other inter-connected outcomes. ADSC adipose-derived stromal cell, bFGF basic fibroblast growth factor, EC endothelial cell, EPC endothelial progenitor cell, GF growth factor, IGF-1 insulin-like growth factor-1, MMP matrix metalloproteinase, PDGF platelet-derived growth factor, RBC red blood cell, SVF stromal vascular fraction, VEGF vascular endothelial growth factor

Full size image

ADSCs in SVF are currently defined to be positive for classical MSC markers such as CD73 and CD90, and express CD34 but not the pan-haematopoietic lineage marker CD45. CD34 is expressed by progenitors of haematopoietic and endothelial lineages as well, and in ADSCs it is expressed transiently up to about 8–12 population doublings in culture [1].The case of CD34 is interesting since it is still largely considered to be a marker for HSCs owing to its historical association with the enrichment of such cells for bone marrow and umbilical cord blood transplantation. Even the pericytic theory related to MSCs and ADSCs has two sides [50]; whereas Crisen et al. attribute CD34– pericytes to be the progenitors of such stromal cells [51], Traktuev et al. demonstrated a CD34+ pericytic identity for ADSCs [46]. Maumus et al. tried to investigate this further but found that native CD34+ ADSCs did not exhibit in vivo pericytic markers, but they were rather observed over the course of the culture process [52]. Our data also show that both manually isolated and Stempeutron™-isolated SVF contains a CD146+ pericytic population that are mostly (>90%) CD34– [29], suggesting that freshly isolated SVF contains a pericytic population devoid of expressing both CD34 and CD31 markers. Whether the CD146+ cells observed within the SVF population subsequently become CD34+ ADSCs remains to be determined. Considerable evidence also exists in favour of CD34 expression in bone marrow-derived MSCs (BMMSCs), especially in the early stages of BMMSC research which included data on the disappearance of CD34 upon culturing [53]. Many aspects of this puzzle are yet to be solved, but it is probable that CD34 marks different progenitor cell types such as different MSCs and vascular endothelial progenitor cells.

In the course of preparing this review, it was also observed that reports of ADSC function and physiology in vitro is minimal and in vivo and/or in the native state is rare and in need of further investigation. Table 2 summarises the observations about the characteristics of ADSCs in situ, in vivo, and in vitro that has been discussed within the review [1, 34,35,36, 46, 47, 52].

Table 2 Overview of characteristics of native and culture expanded ADSCs
Full size table

The curious case of CD34

ADSC research, being predominantly carried out using culture-expanded cells, has led to rather recent acceptance of CD34 as a marker for freshly isolated and native ADSCs. Thus, there remain interesting aspects of CD34 biology to be explored and understood. Firstly, CD34 expression has been associated with “stemness” in various systems including human ADSCs. A report by Suga et al. implied association of CD34 expression with naivety, angiogenic gene expression, and greater replicative capacity [54]. Similar to HSCs, reversal of CD34 expression has also been observed in MSCs with a change in culture conditions, thus hinting that CD34 expression might be reversible [53, 54]. Maumus et al. demonstrated an inverse relationship between CD34 expression and in vitro expansion of ADSCs and provided evidence for CD34 being a niche-specific marker of human ADSCs [52]. Interestingly, they commented on the morphological features of ADSCs in vivo, that is having up to 80-μm long protrusions, capable of forming networks surrounding mature adipocytes; however, the scientific and anatomical reason for these structural features are poorly understood. Taking these into account has led to speculation that CD34 is a physiological niche-specific marker of immature/early progenitor cells which is lost in in-vitro conditions [52,53,54,55,56]. Scherberich et al. review CD34 biology in general and with regards to ADSCs in detail [56].

The second interesting aspect is the relationship between CD34 and hypoxia. Since CD34 might be a niche-specific marker of progenitors, it can be speculated that hypoxic conditions might have something to do with its expression. Hypoxia is related to maintenance of adult stem cells such as those in bone marrow and neural stem cells [57]. In MSCs, and also recently in ADSCs, hypoxic pre-conditioning/culturing has shown improved results with regards to proliferation, retention of transplant, angiogenesis, and modulation of angiogenic factors such as VEGF and interleukin (IL)-6, homing, and mobilisation-related characteristics of MSCs/ADSCs, and so forth [58,59,60,61,62,63]. It is important to note that the ADSC study specifically selected for CD34– cells to begin with and subsequently did not find any significant expression of CD34 in their hypoxically cultured cells [63]. On the other hand, there was a study which speculated that the CD34 gene might be transcriptionally regulated by hypoxia inducible factor 1 (HIF1). The researchers observed that the concentration of oxygen in culture not only influenced the expression of CD34 but also that better maintenance of the antigen corresponded with more undifferentiated cells, which led them to hypothesise that CD34 and hypoxia play an important and inter-related function in maintenance of primitive stem cells of cord blood [64].

Such observations give a certain level of enigma; clearly CD34 and hypoxia are important factors in the maintenance of “stemness”, and it is also likely that CD34 expression is somehow related to hypoxic conditions in different stem or progenitor cell types. However, such a connection remains to be mechanistically studied in human ADSCs, or any other kind of MSCs for that matter. Such studies might provide evidence connecting CD34 with more naive/primitive stem cells, maintained in a hypoxic niche.

Current state in the clinic and laboratory

The first clinical applications of SVF were reported around 2007 to 2008 for cosmetic breast augmentation and also in the treatment of radiation injury post-radiotherapy in breast cancer patients [14, 65]. The Yoshimura group coined the term CAL, or cell-assisted lipotransfer, in 2008, where they enhanced fat grafts with SVF, demonstrating improved graft retention [14, 17]. Since these two early clinical reports from the last decade, there has been a many-fold increase in basic research and, consequently, many clinical trials are also now underway.

Searching www.ClinicalTrials.gov with keywords such as “SVF”, “Stromal vascular fraction”, “ADSC”, “Adipose stem cells”, and so forth, provides many hits. Although most of those studies are underway or recruiting at the time of this communication, interest has been rising with time. What is truly exciting is the breadth of conditions being targeted by SVF and ADSCs. Despite having properties like MSCs, the use of culture-expanded ADSCs has not reached similar consensus for allogeneic applications. However, ADSCs and SVF have been the preferred regenerative tools for use in autologous applications, and some of the major ones (along with case study references and/or ClinicalTrials.gov identification number) are listed in Table 3 [10, 14, 16, 23, 30, 31, 65,66,67,68,69,70,71,72,73,74,75,76]. Some other major ailments covered are pulmonary diseases, arterial and vascular diseases, graft versus host disease, Crohn’s disease, peripheral nerve regeneration, and so forth. Clinical areas where SVF and ADSCs are used do overlap to a substantial extent. Nevertheless, there are understandable differences between the two, but the few comparative pre-clinical and clinical studies available do not reach a unanimous conclusion. However, to summarise where the field stands as of now, a comparative overview of both modes with a few examples favouring either option is provided in Table 4 [9, 11, 12, 77].

Table 3 Major applications of SVF- and ADSC-based therapeutics with corresponding clinical trials and/or case study references
Full size table
Table 4 Comparative overview of SVF and ADSCs
Full size table

A superficial glance at the treatments highlights the two most preferred pathways, that is employing the vasculogenic and the immunomodulatory properties. We are yet to fully explore the multipotent properties of SVF cells which will only increase the breadth of their application. One recent example of enhanced osteoinduction by using SVF for dental implant surgery in human subjects provides encouraging results, wherein researchers found bone formation on implanting artificial graft material with SVF supplement compared to the graft alone [66]. The use of matrices/scaffolds and populating those with SVF and/or ADSCs is a promising area of application, though still in experimental phases [13, 78, 79]. Here, we will not go into much detail regarding the applications as that has been well accomplished in a recent two-part review [3, 26].

“Fat stem cell” therapies and regulatory scenario

Clinics all across the globe began providing “fat stem cell”-based therapy shortly after its discovery, promising miraculous results and more, but often running into controversies [80,81,82,83,84,85,86]. Such therapies in the US are known to charge anywhere from USD5000 to USD100,000, and, although mostly harmless and sometimes beneficial, there have been reports of vision loss, tumours, and even deaths [80,81,82,83,84,85,86]. Being a major issue in the USA, the FDA had to step in with a draft guideline late in 2014 [87]. These guidelines can be considered in future development of technologies and procedures related to SVF and therapies. Although the “stem cell therapy” genre includes many types of stem cells, ADSCs remain the most marketed variety in the US [88].

The common practices of enzymatic and mechanical disruption of adipose tissue for isolating SVF are explicitly mentioned in the FDA document as “more than minimal manipulation” [87]. As and when the guidelines are implemented, SVF isolated by current protocols (enzymatic digestion) can be treated as a Category 351 product, that is a “drug/biologic” and in need of complete FDA regulation [68]. This calls for exploration of alternate methods, keeping in mind that regulations in the US often trickle down to other geographies, especially in matters of food and drugs.

Introduction of the Reliable and Effective Growth for Regenerative Health Options that Improve Wellness (REGROW) Act [89] in the US Senate last year led to scientific and policy debate, with prominent organisations such as the ISCT, the International Society for Stem Cell Research (ISSCR), and many patient and advocacy groups refusing to support it, at least in its current form [88, 90,91,92,93,94]. The REGROW Act aims to hasten the “conditional approval” of certain cell and tissue therapeutic products which demonstrate “reasonable expectation of effectiveness” along with a few other criteria [89]. However, the use of open-ended terms such as “reasonable expectation of effectiveness” amounts to a lack of clear scientific definition, thus leaving scope for interpretation of the law, consequently leading to potential abuse; such concerns are possibly behind this strong opposition towards the act.

Nevertheless, an urgent consensus is required among all stakeholders with regards to realising the translational potential of stem cells and other cell-based therapeutics, especially when it comes to serious unmet medical needs.

Conclusions

MSCs have been long known for their remarkable properties when it comes to regeneration and therapeutic potential. ADSCs are possibly the easiest to isolate among all the different types of MSCs in an adult human and in relative abundance too; up to 500 times more stem/stromal cells per gram as compared to a bone marrow source [95]. Simply put, ADSCs are potentially the most abundant regenerative cells in the human body and SVF is a step in the protocol to isolate ADSCs. As has been repeatedly mentioned in this review, the potential for use of both SVF and ADSCs in regenerative medicine are immense. However, care must be taken to go about it without harming the intended beneficiary, that is the patients and public in general. Guidelines, such as the ones from US FDA and their counterparts elsewhere will be important parameters in judging new therapies and technologies being developed, and we ought to keep abreast of such issues. Technology development is the single most important factor to realise the full potential of any new therapy, and SVF-based therapy is no exception. At the same time, it is evident that we need a better understanding of SVF and ADSC biology. This is a continuous endeavour and will only help to better establish the core principles and mechanisms of SVF- and ADSC-based therapies. In the process, we are likely to discover newer applications apart from the plethora already identified. Combining these therapies with other technologies such as decellularised or three-dimensional printed scaffolds with the aim of transplantation will jump-start other areas of clinical and commercial developments.

Abbreviations

ADSC:

Adipose-derived stem/stromal cell

BADSC:

Brown adipose-derived stem cell

BAT:

Brown adipose tissue

BMMSC:

Bone marrow mesenchymal stromal/stem cell

CAL:

Cell-assisted lipotransfer

CD:

Cluster of differentiation

EC:

Endothelial cell

EPC:

Endothelial precursor cell

FDA:

Food and Drug Administration

HIF1:

Hypoxia inducible factor 1

HSC:

Haematopoietic stem cell

IFATS:

International Federation for Adipose Therapeutics and Science

IL:

Interleukin

ISCT:

International Society of Cellular Therapy

ISSCR:

International Society for Stem Cell Research

MSC:

Mesenchymal stem/stromal cell

PDGF:

Platelet-derived growth factor

REGROW:

Reliable and Effective Growth for Regenerative Health Options that Improve Wellness

SVF:

Stromal vascular fraction

VEGF:

Vascular endothelial growth factor

VLS:

Vulvar lichen sclerosus

WAT:

White adipose tissue

References

  1. Bourin P, Bunnell BA, Casteilla L, et al. Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells: a joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). Cytotherapy. 2013;15:641–8.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Gimble JM, Bunnell BA, Frazier T, et al. Adipose-derived stromal/stem cells. Organogenesis. 2013;9:3–10.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Nguyen A, Guo J, Banyard DA, et al. Stromal vascular fraction: a regenerative reality? Part 1: current concepts and review of the literature. J Plast Reconstr Aesthetic Surg. 2016;69:170–9.

    Article  Google Scholar 

  4. Bunnell B, Flaat M, Gagliardi C, et al. Adipose-derived stem cells: isolation, expansion and differentiation. Methods. 2008;45:115–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Casteilla L. Adipose-derived stromal cells: their identity and uses in clinical trials, an update. World J Stem Cells. 2011;3:25.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Suzuki E, Fujita D, Takahashi M, et al. Adipose tissue-derived stem cells as a therapeutic tool for cardiovascular disease. World J Cardiol. 2015;7:454–65.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Bony C, Cren M, Domergue S, et al. Adipose mesenchymal stem cells isolated after manual or water-jet-assisted liposuction display similar properties. Front Immunol. 2016;6:1–8.

    Article  Google Scholar 

  8. Mi HM, Sun YK, Yeon JK, et al. Human adipose tissue-derived mesenchymal stem cells improve postnatal neovascularization in a mouse model of hindlimb ischemia. Cell Physiol Biochem. 2006;17:279–90.

    Article  Google Scholar 

  9. van Dijk A, Naaijkens BA, Jurgens WJFM, et al. Reduction of infarct size by intravenous injection of uncultured adipose derived stromal cells in a rat model is dependent on the time point of application. Stem Cell Res. 2011;7:219–29.

    Article  PubMed  Google Scholar 

  10. Charles-de-Sá L, Gontijo-de-Amorim NF, Maeda Takiya C, et al. Antiaging treatment of the facial skin by fat graft and adipose-derived stem cells. Plast Reconstr Surg. 2015;135:999–1009.

    Article  PubMed  Google Scholar 

  11. Semon JA, Zhang X, Pandey AC, et al. Administration of murine stromal vascular fraction ameliorates chronic experimental autoimmune encephalomyelitis. Stem Cells Transl Med. 2013;2:789–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. You D, Jang MJ, Kim BH, et al. Comparative study of autologous stromal vascular fraction and adipose-derived stem cells for erectile function recovery in a rat model of cavernous nerve injury. Stem Cells Transl Med. 2015;4:351–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mohammadi R, Sanaei N, Ahsan S, et al. Stromal vascular fraction combined with silicone rubber chamber improves sciatic nerve regeneration in diabetes. Chinese J Traumatol. 2015;18:212–8.

    Article  Google Scholar 

  14. Yoshimura K, Sato K, Aoi N, et al. Cell-assisted lipotransfer for cosmetic breast augmentation: supportive use of adipose-derived stem/stromal cells. Aesthetic Plast Surg. 2008;32:48–55.

    Article  PubMed  Google Scholar 

  15. Pak J, Chang J-J, Lee JH, et al. Safety reporting on implantation of autologous adipose tissue-derived stem cells with platelet-rich plasma into human articular joints. BMC Musculoskelet Disord. 2013;14:337.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Yoshimura K, Suga H, Eto H. Adipose-derived stem/progenitor cells: roles in adipose tissue remodeling and potential use for soft tissue augmentation. Regen Med. 2009;4:265–73.

    Article  PubMed  Google Scholar 

  17. Matsumoto D, Sato K, Gonda K, et al. Cell-assisted lipotransfer: supportive use of human adipose-derived cells for soft tissue augmentation with lipoinjection. Tissue Eng. 2006;12:3375–82.

    Article  CAS  PubMed  Google Scholar 

  18. Silva FJ, Holt DJ, Vargas V, et al. Metabolically active human brown adipose tissue derived stem cells. Stem Cells. 2014;32:572–81.

    Article  CAS  PubMed  Google Scholar 

  19. Gimble JM, Katz AJ, Bunnell BA. Adipose-derived stem cells for regenerative medicine. Circ Res. 2007;100:1249–60.

    Article  CAS  PubMed  Google Scholar 

  20. Colen BD. A pill to shed fat? Harvard stem cell researchers say they finally can turn “bad” fat into “good.” Harvard Gaz 2014. http://news.harvard.edu/gazette/story/2014/12/a-pill-to-shed-fat/. Accessed 8 Sept 2016.

  21. Moisan A, Lee Y-K, Zhang JD, et al. White-to-brown metabolic conversion of human adipocytes by JAK inhibition. Nat Cell Biol. 2014;17:57–67.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Oberbauer E, Steffenhagen C, Wurzer C, et al. Enzymatic and non-enzymatic isolation systems for adipose tissue-derived cells: current state of the art. Cell Regen. 2015;4:7.

    Article  Google Scholar 

  23. Tonnard P, Verpaele A, Peeters G, et al. Nanofat grafting: basic research and clinical applications. Plast Reconstr Surg. 2013;132:1017–26.

    Article  CAS  PubMed  Google Scholar 

  24. Aronowitz JA, Lockhart RA, Hakakian CS. Mechanical versus enzymatic isolation of stromal vascular fraction cells from adipose tissue. Springerplus. 2015;4:713.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Shah FS, Wu X, Dietrich M, et al. A non-enzymatic method for isolating human adipose tissue-derived stromal stem cells. Cytotherapy. 2013;15:979–85.

    Article  CAS  PubMed  Google Scholar 

  26. Guo J, Nguyen A, Banyard DA, et al. Stromal vascular fraction: a regenerative reality? Part 2: mechanisms of regenerative action. J Plast Reconstr Aesthetic Surg. 2016;69:180–8.

    Article  Google Scholar 

  27. Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8:315–7.

    Article  CAS  PubMed  Google Scholar 

  28. Zuk PA, Zhu M, Mizuno H, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001;7:211–28.

    Article  CAS  PubMed  Google Scholar 

  29. SundarRaj S, Deshmukh A, Priya N, et al. Development of a system and method for automated isolation of stromal vascular fraction from adipose tissue lipoaspirate. Stem Cells Int. 2015;2015:1–11.

    Article  Google Scholar 

  30. Riis S, Zachar V, Boucher S, et al. Critical steps in the isolation and expansion of adipose-derived stem cells for translational therapy. Expert Rev Mol Med. 2015;17:e11.

    Article  CAS  PubMed  Google Scholar 

  31. Tamburino S, Lombardo GA, Tarico MS, et al. The role of nanofat grafting in vulvar lichen sclerosus: a preliminary report. Arch Plast Surg. 2016;43:93.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Kemaloğlu CA. Nanofat grafting under a split-thickness skin graft for problematic wound management. Springerplus. 2016;5:138.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Fraser JK, Hicok KC, Shanahan R, et al. The Celution(®) system: automated processing of adipose-derived regenerative cells in a functionally closed system. Adv Wound Care. 2014;3:38–45.

    Article  Google Scholar 

  34. Invitrogen™ Countess™. Invitrogen cell data sheet-ADSC. http://www.thermofisher.com/content/dam/LifeTech/migration/en/filelibrary/cell-tissue-analysis/pdfs.par.71179.file.dat/co13964-stem-cell-data-sheet-adsc.pdf. Accessed 7 Sept 2016.

  35. Sponsored paper. Rapid analysis of human adipose-derived stem cells and 3 T3-L1 differentiation toward adipocytes using the Scepter™ 2.0 cell counter. Biotechniques. 2012;53:109–11.

  36. Ryu YJ, Cho TJ, Lee DS, et al. Phenotypic characterization and in vivo localization of human adipose-derived mesenchymal stem cells. Mol Cells. 2013;35:557–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Asahara T, Kawamoto A, Masuda H. Concise review: circulating endothelial progenitor cells for vascular medicine. Stem Cells. 2011;29:1650–5.

    Article  CAS  PubMed  Google Scholar 

  38. Garipcan B, Maenz S, Pham T, et al. Image analysis of endothelial microstructure and endothelial cell dimensions of human arteries—a preliminary study. Adv Eng Mater. 2011;13:B54–7.

    Article  Google Scholar 

  39. Bergman RA, Afifi AK, Heidger PM. Anatomy atlases: atlas of microscopic anatomy: section 4—blood. Plate 4.53: lymphocytes. http://www.anatomyatlases.org/MicroscopicAnatomy/Section04/Plate0453.shtml. Accessed 7 Sept 2016.

  40. Rosenbluth MJ, Lam WA, Fletcher DA. Force microscopy of nonadherent cells: a comparison of leukemia cell deformability. Biophys J. 2006;90:2994–3003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Krombach F, Münzing S, Allmeling AM, et al. Cell size of alveolar macrophages: an interspecies comparison. Environ Health Perspect. 1997;105:1261–3.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Duke University Medical School. Histology learning resources. https://web.duke.edu/histology/MoleculesCells/Muscle/Muscle.html#webslide96. Accessed 7 Sept 2016.

  43. Duke University Medical School. Histology learning resources. https://web.duke.edu/histology/MoleculesCells/Muscle/muscle.jpg. Accessed 7 Sept 2016.

  44. Proebstl D, Voisin M-B, Woodfin A, et al. Pericytes support neutrophil subendothelial cell crawling and breaching of venular walls in vivo. J Exp Med. 2012;209:1219–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Lai N, Sims JK, Jeon NL, et al. Adipocyte induction of preadipocyte differentiation in a gradient chamber. Tissue Eng Part C Methods. 2012;18:958–67.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Traktuev DO, Merfeld-Clauss S, Li J, et al. A population of multipotent CD34-positive adipose stromal cells share pericyte and mesenchymal surface markers, reside in a periendothelial location, and stabilize endothelial networks. Circ Res. 2008;102:77–85.

    Article  CAS  PubMed  Google Scholar 

  47. Traktuev DO, Prater DN, Merfeld-Clauss S, et al. Robust functional vascular network formation in vivo by cooperation of adipose progenitor and endothelial cells. Circ Res. 2009;104:1410–20.

    Article  CAS  PubMed  Google Scholar 

  48. Pallua N, Serin M, Wolter TP. Characterisation of angiogenetic growth factor production in adipose tissue-derived mesenchymal cells. J Plast Surg Hand Surg. 2014;48:412–6.

    Article  PubMed  Google Scholar 

  49. Grasys J, Kim B, Pallua N. Content of soluble factors and characteristics of stromal vascular fraction cells in lipoaspirates from different subcutaneous adipose tissue depots. Aesthetic Surg J. 2016;36:831–41.

    Article  Google Scholar 

  50. Szöke K, Brinchmann JE. Concise review: therapeutic potential of adipose tissue-derived angiogenic cells. Stem Cells Transl Med. 2012;1:658–67.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Crisan M, Yap S, Casteilla L, et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell. 2008;3:301–13.

    Article  CAS  PubMed  Google Scholar 

  52. Maumus M, Peyrafitte J-A, D’Angelo R, et al. Native human adipose stromal cells: localization, morphology and phenotype. Int J Obes. 2011;35:1141–53.

    Article  CAS  Google Scholar 

  53. Lin C-S, Ning H, Lin G, et al. Is CD34 truly a negative marker for mesenchymal stromal cells? Cytotherapy. 2012;14:1159–63.

    Article  CAS  PubMed  Google Scholar 

  54. Suga H, Matsumoto D, Eto H, et al. Functional implications of CD34 expression in human adipose–derived stem/progenitor cells. Stem Cells Dev. 2009;18:1201–10.

    Article  CAS  PubMed  Google Scholar 

  55. Sidney LE, Branch MJ, Dunphy SE, et al. Concise review: evidence for CD34 as a common marker for diverse progenitors. Stem Cells. 2014;32:1380–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Scherberich A, Di Maggio N, McNagny KM. A familiar stranger: CD34 expression and putative functions in SVF cells of adipose tissue. World J Stem Cells. 2013;5:1–8.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Keith B, Simon MC. Hypoxia-inducible factors, stem cells, and cancer. Cell. 2007;129:465–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Das R, Jahr H, van Osch GJVM, et al. The role of hypoxia in bone marrow-derived mesenchymal stem cells: considerations for regenerative medicine approaches. Tissue Eng Part B Rev. 2010;16:159–68.

    Article  CAS  PubMed  Google Scholar 

  59. Ejtehadifar M, Shamsasenjan K, Movassaghpour A, et al. The effect of hypoxia on mesenchymal stem cell biology. Adv Pharm Bull. 2015;5:141–9.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Beegle J, Lakatos K, Kalomoiris S, et al. Hypoxic preconditioning of mesenchymal stromal cells induces metabolic changes, enhances survival, and promotes cell retention in vivo. Stem Cells. 2015;33:1818–28.

    Article  CAS  PubMed  Google Scholar 

  61. Haque N, Rahman MT, Abu Kasim NH, et al. Hypoxic culture conditions as a solution for mesenchymal stem cell based regenerative therapy. Sci World J. 2013;2013:1–12.

    Article  Google Scholar 

  62. Grayson WL, Zhao F, Bunnell B, et al. Hypoxia enhances proliferation and tissue formation of human mesenchymal stem cells. Biochem Biophys Res Commun. 2007;358:948–53.

    Article  CAS  PubMed  Google Scholar 

  63. Feng Y, Zhu M, Dangelmajer S, et al. Hypoxia-cultured human adipose-derived mesenchymal stem cells are non-oncogenic and have enhanced viability, motility, and tropism to brain cancer. Cell Death Dis. 2014;5:e1567.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Brunet De La Grange P, Barthe C, Lippert E, et al. Oxygen concentration influences mRNA processing and expression of the CD34 gene. J Cell Biochem. 2006;97:135–44.

    Article  PubMed  Google Scholar 

  65. Rigotti G, Marchi A, Galie M, et al. Clinical treatment of radiotherapy tissue damage by lipoaspirate transplant: a healing process mediated by adipose-derived adult stem cells. Plast Reconstr Surg. 2007;119:1409–22.

    Article  CAS  PubMed  Google Scholar 

  66. Prins H-J, Schulten EAJM, ten Bruggenkate CM, et al. Bone regeneration using the freshly isolated autologous stromal vascular fraction of adipose tissue in combination with calcium phosphate ceramics. Stem Cells Transl Med. 2016;5:1362–74.

    Article  PubMed  Google Scholar 

  67. Haahr MK, Jensen CH, Toyserkani NM, et al. Safety and potential effect of a single intracavernous injection of autologous adipose-derived regenerative cells in patients with erectile dysfunction following radical prostatectomy: an open-label phase I clinical trial. EBioMedicine. 2016;5:204–10.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Tocco I, Widgerow AD, Lalezari S, et al. Lipotransfer: the potential from bench to bedside. Ann Plast Surg. 2014;72:599–609.

    Article  CAS  PubMed  Google Scholar 

  69. Doi K, Tanaka S, Iida H, et al. Stromal vascular fraction isolated from lipo-aspirates using an automated processing system: bench and bed analysis. J Tissue Eng Regen Med. 2013;7:864–70.

    Article  CAS  PubMed  Google Scholar 

  70. Rigotti G, Charles-de-Sá L, Gontijo-de-Amorim NF, et al. Expanded stem cells, stromal-vascular fraction, and platelet-rich plasma enriched fat: comparing results of different facial rejuvenation approaches in a clinical trial. Aesthet Surg J. 2016;36:261–70.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Jackson WM, Nesti LJ, Tuan RS. Concise review: clinical translation of wound healing therapies based on mesenchymal stem cells. Stem Cells Transl Med. 2012;1:44–50.

    Article  CAS  PubMed  Google Scholar 

  72. Borowski DW, Gill TS, Agarwal AK, et al. Autologous adipose-tissue derived regenerative cells for the treatment of complex cryptoglandular fistula-in-ano: a report of three cases. BMJ Case Rep. 2012;2012:4–7.

    Article  Google Scholar 

  73. Riordan NH, Ichim TE, Min W-P, et al. Non-expanded adipose stromal vascular fraction cell therapy for multiple sclerosis. J Transl Med. 2009;7:29.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Lee HC, An SG, Lee HW, et al. Safety and effect of adipose tissue-derived stem cell implantation in patients with critical limb ischemia. Circ J. 2012;76:1750–60.

    Article  CAS  PubMed  Google Scholar 

  75. Parcero JJ, Perez JA, Patel AN, et al. Autologous adipose-derived stromal stem cell implantation to resolve critical limb ischemia: case report. Cureus. 2014;6(5):e182. doi:10.7759/cureus.182. http://www.cureus.com/articles/2376-autologous-adipose-derived-stromal-stem-cell-implantation-to-resolve-critical-limb-ischemia-case-report.

  76. Pers Y-M, Rackwitz L, Ferreira R, et al. Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: a phase I dose-escalation trial. Stem Cells Transl Med. 2016;5:847–56.

    Article  PubMed  Google Scholar 

  77. Domergue S, Bony C, Maumus M, et al. Comparison between stromal vascular fraction and adipose mesenchymal stem cells in remodeling hypertrophic scars. PLoS One. 2016;11:e0156161.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Frazier TP, Bowles A, Lee S, et al. Serially transplanted nonpericytic CD146– adipose stromal/stem cells in silk bioscaffolds regenerate adipose tissue in vivo. Stem Cells. 2016;34:1097–111.

    Article  CAS  PubMed  Google Scholar 

  79. Lin S-D, Huang S-H, Lin Y-N, et al. Injected implant of uncultured stromal vascular fraction loaded onto a collagen gel. Ann Plast Surg. 2016;76:S108–16.

    Article  CAS  PubMed  Google Scholar 

  80. NEWSmax. Unregulated stem cell industry is “wild west.” NEWSmax; 2015. http://www.newsmax.com/Health/Health-News/stem-cells-treatments-regulation/2015/05/18/id/645186/. Accessed 7 Sept 2016.

  81. McFarling UL. FDA moves to crack down on unproven stem cell therapies. STAT News. 2016. https://www.statnews.com/2016/02/08/fda-crackdown-stem-cell-clinics/. Accessed 7 Sept 2016.

  82. Jabr F. In the flesh: the embedded dangers of untested stem cell cosmetics. Sci Am. 2012. Available at http://www.scientificamerican.com/article/stem-cell-cosmetics/. Accessed 7 Sept 2016.

  83. Wilson C. Stem cell treatment causes nasal growth in woman’s back. New Sci. 2014. https://www.newscientist.com/article/dn25859-stem-cell-treatment-causes-nasal-growth-in-womans-back/. Accessed 7 Sept 2016.

  84. Cyranoski D. Korean deaths spark inquiry. Nature. 2010;468:485.

    Article  CAS  PubMed  Google Scholar 

  85. McLean AK, Stewart C, Kerridge I. Untested, unproven, and unethical: the promotion and provision of autologous stem cell therapies in Australia. Stem Cell Res Ther. 2015;6:12.

    Article  PubMed Central  Google Scholar 

  86. Ledford H. Boom in unproven cell therapies intensifies regulatory debate. Nature. 2016;537:148.

    Article  CAS  PubMed  Google Scholar 

  87. US Department of Health and Human Services (Food and Drug Administration). Human cells, tissues, and cellular- and tissue-based products (HCT/Ps) from adipose tissue : regulatory considerations; draft guidance. http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Tissue/ucm427795.htm#HCT_QUESTION. Accessed 7 Sept 2016.

  88. Turner L, Knoepfler P. Selling stem cells in the USA: assessing the direct-to-consumer industry. Cell Stem Cell. 2016;19:154–7.

    Article  CAS  PubMed  Google Scholar 

  89. Kirk MS, Manchin J, Collins SM. REGROW Act. Congress.gov 2016. https://www.congress.gov/bill/114th-congress/senate-bill/2689/cosponsors. Accessed 7 Sept 2016.

  90. Research MJFF for P. MJFF signs letter opposing the REGROW Act 2016. https://www.michaeljfox.org/foundation/news-detail.php?mjff-signs-letter-opposing-the-regrow-act. Accessed 7 Sept 2016.

  91. International Society for Cellular Therapy. ISCT calls for changes to proposed US REGROW Act on cell therapies 2016. http://www.celltherapysociety.org/news/news.asp?id=304128&hhSearchTerms=%22regrow%22. Accessed 7 Sept 2016.

  92. The Alliance for Regenerative Medicine. ARM statement in response to U.S. Senator Kirk’s REGROW Act. http://alliancerm.org/sites/default/files/ARMSenatorKirk_REGROWActletter_March2016_.pdf. Accessed 7 Sept 2016.

  93. Knoepfler P. California stem-cell institute’s political gamble. San Fr Chron 2016. http://www.sfchronicle.com/opinion/article/California-stem-cell-institute-s-political-8250137.php?t=4c01ff1973cefdcb88&cmpid=twitter-premium. Accessed 7 Sept 2016.

  94. Joseph A. Drive to get more patients experimental stem cell treatments stirs concern. STAT News 2016. https://www.statnews.com/2016/06/30/stem-cell-political-fight. Accessed 7 Sept 2016.

  95. Hass R, Kasper C, Böhm S, et al. Different populations and sources of human mesenchymal stem cells (MSC): a comparison of adult and neonatal tissue-derived MSC. Cell Commun Signal. 2011;9:12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Dr. Swathi SundarRaj and Mr. Murali Cherat for critical reading of the manuscript and feedback, and members of Stempeutics, especially Mr. Vasanth Kumar, Ms. Pradnya Shahani, and Ms. Ankita Walvekar along with the rest of the Research & Development division for their help and support during writing of this review.

Funding

Not applicable.

Availability of data and materials

Not applicable.

Authors’ contributions

PB: Conceptualisation, data mining, and writing of manuscript. ASM: Conceptualisation, manuscript review, editing suggestions, and final approval. Both authors read and approved the final manuscript.

Competing interests

PB and ASM are or have been part of Stempeutics Research and were involved in the development of Stempeutron™ as salaried employees of Stempeutics Research Pvt. Ltd.

Consent for publication

The Tables and the Figure are original for this article and the sources used have been cited both within the article and within the Tables and Figure.

Ethics approval and consent to participate

Not applicable.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Author information

Authors and Affiliations

  1. Stempeutics Research Private Limited, Akshay Tech Park, # 72&73, 2nd Floor, EPIP Zone, Phase 1, Whitefield, Bangalore, 560066, India

    Pablo Bora & Anish S. Majumdar

  2. Present Address: Department of Molecular Biology & Genetics, Faculty of Science, Jihočeská univerzita v Českých Budějovicích (University of South Bohemia), Branišovská 31, 37005, České Budějovice, Czech Republic

    Pablo Bora

Authors
  1. Pablo Bora
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anish S. Majumdar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anish S. Majumdar.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), 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 (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bora, P., Majumdar, A.S. Adipose tissue-derived stromal vascular fraction in regenerative medicine: a brief review on biology and translation. Stem Cell Res Ther 8, 145 (2017). https://doi.org/10.1186/s13287-017-0598-y

Download citation

  • Published:

  • DOI: https://doi.org/10.1186/s13287-017-0598-y

Keywords

Stem Cell Research & Therapy

ISSN: 1757-6512