Table 2 Small molecule enhancers of MSC efficacy

Valproic acid + sphingosine-1-phosphate

In vitro

Enhanced migration, proliferation, colony forming units. Anti-inflammatory properties

Lim et al. [103]

Desferrioxamine (DFO)

In vitro

Low dose led to reduced mitochondrial activity and apoptosis of MSCs

Fujisawa et al. [97]

Dimethyloxalylglycine (DMOG)

In vitro

In vivo

Increased cell survival and pro-angiogeneic factors (HIF-1α, VEGF). In vivo (rat myocardial infarction model) DMOG-MSCs reduced heart infarct size with improved therapeutic benefits

Liu et al. [101]

Anesthetic isoflurane

In vitro

In vivo

Short low dose exposure enhanced MSC survival and migration. Upregulated HIF-1α, SDF-1, CXCR4. Activation of Akt similar to hypoxia treatment. In vivo (Rat middle cerebral artery occlusion model) isoflurane priming enhanced MSC engraftment in ischemic brain and improved outcome in mouse model of stroke

Sun et al. [100]

All-trans retinoic acid (ATRA)

In vitro

In vivo

ATRA increased MSC expression of cell survival and growth factors (COX-2, HIF-1α, CXCR4, CCR2, VEGF, Ang-2, Ang-4). In vivo (rat wound healing model) ATRA primed MSCs were superior in wound closure with improved angiogenesis

Pourjafar et al. [99]

Rapamycin, everolimus, FK506 or cyclosporine A

In vitro

In vivo

Immunosuppressant treated MSCs fivefold more suppressive of T-cell proliferation in vitro. MSCs adsorbed and released drugs to host cells in vitro. In vivo (humanised GvHD mouse model) low dose primed MSCs significantly inhibited onset of disease compared to untreated MSCs

Girdlestone et al. [104]

Adenosine receptor activation

In vitro

Activation of A1R (via 2-chloro-N6-cyclopentyl-adenosine (CCPA)) led to greater osteogenic differentiation via induction of osteogenic markers RUNX2 & alkaline phosphate (ALP) & mineralisation of extracellular matrix

D'Alimonte et al. [105]

Rapamycin

In vitro

Short but not long incubation with rapamycin enhanced MSC immunosuppressive effect. Effect mainly via upregulation of COX-2 and PGE2. mTOR inhibition significantly reduced IFN-γ induced MHC-II on MSC

Wang et al. [106]

2,4-dinitrophenol (DNP)

In vitro

In vivo

In vitro enhanced expression of cardiomyogenesis, cell adhesion and angiogenesis genes. Intra-myocardial transplantation of DNP pre-conditioned MSCs led to enhanced adhesion to myocardial surface with more viable cells. Improvement in cardiac function, less scar formation, enhanced maintenance of left ventricular wall thickness and increased angiogenesis

Khan et al. [96]

All-trans retinoic acid (ATRA)

In vitro

ATRA treated MSCs in co-culture assays with AS patient’s PBMCs. Enhanced MSC IL-6 secretion. ATRA treated MSCs reduced Th17, T-regs, TNF-α, IFN-γ

Li et al. [102]

5-aza-2′-deoxycytidine (5-aza-dC)

In vitro

Methyltransferase inhibitor 5-aza-dC elevated endothelial markers (CD31, CD105, eNOS, VE-cadherin), promoted angiogenesis in matrigel assays. Upregulated endothelial differentiation inducers (VEGFA, ANGPT2, FGF2, FGF9 and ETS1)

Xu et al. [107]

All-trans retinoic acid (ATRA)

In vivo

In vivo (mouse elastase induced emphysema model) ATRA + MSCs combination increased static lung compliance, mean linear intercepts & alveolar surface area. P70S6 Kinase-1 overexpressing MSCs + ATRA even more beneficial. ATRA activated P70S6Kinase-1 enhanced accumulation and extended survival of MSCs

Takeda et al. [98]

β3 adrenergic agonists (β3AR)

In vivo

Agonist with CXCR4 antagonist mobilised MSCs to blood stream in rodents. Reversal of CXCL12 gradient across bone marrow endothelium and production of endocannabinoids. Significant induction of bone formation in rat spine fusion model

Fellous et al. [108]

Lithium + valproic acid

In vivo

Intranasal delivery of lithium and valproic acid treated MSCs in Huntington’s disease mouse model enhanced open field test, ambulatory distance and mean velocity. Benefits to motor function, reduced striatal neuronal loss and Huntington aggregates versus naïve MSCs. Increased MSC trophic effects, antioxidants, cytokine/chemokine receptors, migration, mitochondrial energy metabolism and stress response signaling pathways. Pre-treated MSCs survived longer after transplantation

Linares et al. [95]