Mesenchymal stem cells in the treatment of spinal cord injuries: A review

Table 1 Overview of effects of bone marrow stromal cells after spinal cord injury

Source of MSC	Main pathological features improved/repaired	Limitations/recommendations/conclusions	Ref.
Human	Axonal growth, partial recovery of function	Differences in donor or lot-lot efficacy of MSC	Neuhuber et al[37], 2005
Human	Axonal growth, significant behavioral recovery	Survival of BMSC grafts for longer duration	Himes et al[38], 2006
Human	Significant motor improvements in human patients	Autologous bone marrow cell transplantation with GM-CSF administration has no serious complications. More comprehensive multicenter clinical studies are recommended	Park et al[52], 2005
Human	Homing of MSC, functional recovery	Mechanisms of engraftment, homing, long-term safety	Cizkova et al[42], 2006
Rhesus monkey	De novo neurogenesis and functional recovery in rhesus monkeys	Synergetic effects of MSC implantation and locally delivered neurotrophic factors in rhesus SCI models	Deng et al[54], 2006
Pig	Improvement in somatosensory-evoked potentials, functional recovery in pigs	Possible utility of BMSC transplantation in humans suffering from chronic paraplegia	Zurita et al[55], 2008
Rat	No allodynia, anti-inflammatory, increase in white matter volume and decrease in cyst size, sensorimotor enhancements	Survival of MSC	Abrams et al[39], 2009
Rat	MSC form bundles bridging the lesion epicenter, functional recovery	Neuron-like MSC lacked voltage-gated ion channels for generation of action potentials	Hofstetter et al[40], 2002
Rat	Cavity reduction, functional recovery	Unknown trophic factors secreted by BMSC	Ohta et al[41], 2004
Rat	Downregulation of apoptosis, functional recovery	Intrinsic properties of MSC, microenvironment of the injured spinal cord, host-graft interactions	Dasari et al[43], 2007
Rat/gerbil	Activation of survival signaling pathways, neuroprotection	Neuroprotective factors released by BMSC, interactions between neurons and BMSC	Isele et al[44], 2007
Rat	Axonal regeneration, myelination of axons	Resection of the chronic scar
Rat	Increase in spared white matter, functional recovery	Differences in mechanism of action of MSCs or BMCs (bone marrow cells) or G-CSF in inducing functional and morphological improvement	Urdzíková et al[46], 2006
Rat	Reduction in inflammation, promoting angiogenesis, and reducing cavity formation	GS scaffolds may serve as a potential supporting biomaterial for wound healing after SCI	Zeng et al[48], 2011
Rat	Extensive in-growth of serotonin-positive raphaespinal axons and calcitonin gene-related peptide-positive dorsal root sensory axons, attenuation of astroglial and microglial activity	Production of trophic factors support neuronal survival and axonal regeneration	Novikova et al[49], 2011
Rat	Functional recovery	Repetitive IT transplantation may improve behavioral function depending on optimization of dose, timing, and targeted IT delivery of MSCs	Cizkova et al[50], 2011
Rat	Axonal regeneration, functional recovery	Feasibility of therapeutic cell delivery using 3D scaffolds, especially in complete spinal cord transection	Kang et al[51], 2011
Rat	Partial improvement in ASIA score in human patients	Polymer hydrogels may become suitable materials for bridging cavities after SCI	Sykova et al[53], 2006

SCI: Spinal cord injury; MSC: Marrow stromal cell; IT: Intrathecal; CSF: Cerebrospinal fluid; GS: Gelatin sponge; BMSC: Bone marrow-derived mesenchymal stem cell.

Table 2 Overview of effects of Adipose tissue-derived mesenchymal cells after spinal cord injury

Source of MSC	Main pathological features improved/repaired	Limitations/recommendations/conclusions	Ref.
Human	Functional recovery	Interaction between engrafted rATSC-OPCs and endogenous spinal cord-derived NPCs promotes host injury repair	Kang et al[58], 2006
Human	Improvement in both the cell survival and the gene expression of the engineered NSC observed in SCI rats	Hypoxia preconditioning strategy and combined stem cell/gene therapies can be used to augment the therapeutic efficacy at target injury sites	Oh et al[62], 2010
Human	mNSCs transplanted into rat spinal cords with AT-MSCs showed better survival rates than mNSCs transplanted alone	Co-transplantation of mNSCs with AT-MSCs may be a more effective transplantation protocol to improve the survival of cells in the injured cord	Oh et al[63], 2011
Human	Transplantation of 3DCM-ASCs into the injured spinal cord significantly elevated the density of vascular formations and enhanced axonal outgrowth at the lesion site, functional recovery	Transplantation of 3DCM-ASCs may be an effective stem cell therapy	Oh et al[64], 2012
Human	No toxicity of hAdMSCs in immunodeficient mice, none of 8 male patients developed any serious adverse events related to hAdMSC transplantation in phase I clinical trial	Systemic transplantation of hAdMSCs appears to be safe and does not induce tumor development. Slow intravenous infusion of autologous hAdMSCs may be safe in SCI patients	Ra et al[66], 2011
Human	Increase in BDNF levels, increased angiogenesis, preserved axons, decreased numbers of ED1-positive macrophages, reduced lesion cavity formation, functional recovery in rats	Compared with hBMSCs, hADSCs may be a better source of MSCs for cell therapy for acute SCI because of their relative abundance and accessibility	Zhou et al[67], 2013
Dog	Significant improvement in nerve conduction velocity based on SEP, partial improvement in neurological functions of dogs	ASCs in spinal cord injuries might be partially due to neural differentiation of implanted stem cells	Ryu et al[61], 2009
Dog	Anti-inflammation, anti-astrogliosis, neuronal extension, neuronal regeneration, functional recovery	The combination of Matrigel and NMSC produced beneficial effects	Park et al[65], 2012
Rat	Reduced apoptotic cell death, astrogliosis and hypo-myelination, functional recovery	ATSC extracts may provide a powerful autoplastic therapy for neurodegenerative conditions in humans	Kang et al[59], 2007
Rat	Neural differentiated ADSCs did not result in better functional recovery than undifferentiated ones following SCI	In vitro neural transdifferentiation of ADSCs might therefore not be a necessary pre-transplantation step	Zhang et al[60], 2009
Rat	Functional recovery	Predifferentiation of ASCs plays a beneficial role in SCI repair	Arboleda et al[57], 2011
Rat	Axonal regeneration, remyelination, functional recovery	Adipose tissue-derived Schwann cells can support axon regeneration and enhance functional recovery	Zaminy et al[68], 2013

OPCs: Oligodendrocyte precursor cells; NPCs: Neural progenitor cells; NSC: Neural stem cell; SCI: Spinal cord injury; MSC: Marrow stromal cell; AT: Adipose tissue; 3DCM-ASCs: Three-dimensional cell mass transplantation of adipose-derived stem cells; hAdMSCs: Human Adipose tissue-derived mesenchymal stem cells; NMSC: Neural-induced mesenchymal stem cells; ATSC: Adipose tissue stromal cell; ADSCs: Adipose tissue-derived stromal cells; BMSC: Bone marrow-derived mesenchymal stem cell.

Table 3 Changes in the expression of apoptotic genes and inhibitors after spinal cord injury and human umbilical cord blood stem cells treatment

UniGene	GenBank	Gene name	Fold change after SCI	Fold change after hUCBSC treatment
Rn. 36696	NM_022698	Bad	3.12 ± 1.34	-1.47 ± 0.14
Rn. 14598	NM_053812	Bak1	2.28 ± 0.99	1.36 ± 0.79
Rn. 13007	NM_031328	Bcl10	8.83 ± 1.91	1.51 ± 1.45
Rn. 19770	NM_133416	Bcl2a1	7.95 ± 1.98	1.79 ± 0.75
Rn. 10323	NM_031535	Bcl2l1	2.13 ± 0.85	-2.01 ± 0.89
Rn. 162782	NM_022684	Bid	2.45 ± 1.27	1.86 ± 0.99
Rn. 89639	NM_057130	Bid3	5.43 ± 1.06	2.62 ± 0.75
Rn. 38487	NM_053704	Bik	4.41 ± 0.64	3.58 ± 0.14
Rn. 92423	XM_226742	Birc1b	25.84 ± 0.85	3.01 ± 0.67
Rn. 64578	NM_023987	Birc3	10.14 ± 1.06	3.01 ± 0.78
Rn. 54471	NM_022274	Birc5	-2.84 ± 1.98	4.57 ± 1.14
Rn. 55946	NM_057138	Cflar (Flip)	3.12 ± 1.77	-1.20 ± 0.86

Results are expressed as mean ± SD. hUCBSC: Human umbilical cord blood stem cells; SCI: Spinal cord injury. Refer Dasari et al[75].

Table 4 Changes in the expression of caspase-related and nuclear factor-κB-related apoptotic genes after spinal cord injury

UniGene	GenBank	Gene name	Fold change after SCI	Fold change after hUCBSC treatment
Rn. 37508	NM_012762	Casp1	9.14 ± 1.70	1.27 ± 0.78
Rn. 81078	NM_130422	Casp12	2.91 ± 1.34	1.46 ± 0.68
Rn. 10562	NM_012922	Casp3	3.56 ± 0.92	1.18 ± 0.84
Rn. 88160	NM_031775	Casp6	3.34 ± 1.06	1.46 ± 0.79
Rn. 53995	NM_022260	Casp7	2.81 ± 1.27	2.81 ± 1.21
Rn. 54474	NM_022277	Casp8	3.84 ± 1.20	1.62 ± 0.89
Rn. 32199	NM_031632	Casp9	2.86 ± 0.71	1.36 ± 0.62
Rn. 67077	NM_053362	Dffb (Cad)	32.94 ± 0.78	2.72 ± 0.84
Rn. 16183	NM_152937	Fadd	2.21 ± 0.78	1.51 ± 0.73
Rn. 162521	NM_139194	Tnfrsf6 (Fas)	10.87 ± 1.77	1.79 ± 0.67
Rn. 44218	NM_053353	CD40lg	15.91 ± 0.99	3.46 ± 0.78
Rn. 160577	NM_080769	Lta (Tnfb)	28.67 ± 0.07	2.06 ± 0.68
Rn. 2275	NM_012675	TNF-α	7.17 ± 1.63	2.36 ± 1.03
Rn. 11119	NM_013091	Tnfrsf1a (TNFR1)	2.53 ± 1.48	1.22 ± 0.78
Rn. 83633	NM_130426	Tnfrsf1b (TNFR2)	5.25 ± 1.56	3.01 ± 0.99
Rn. 25180	NM_134360	Tnfrsf5 (CD40)	4.26 ± 1.84	1.99 ± 0.78
Rn. 54443	NM_030989	Tp53 (P53)	3.46 ± 1.41	-1.12 ± 0.61
Rn. 18545	XM_341671	Tradd	5.62 ± 1.13	1.46 ± 0.59
Rn. 136874	AI406530	Traf1	4.12 ± 1.34	2.06 ± 0.84

Results are expressed as mean ± SD. hUCBSC: Human umbilical cord blood stem cells; NF-κB: Nuclear factor-κB; SCI: Spinal cord injury. Refer Dasari et al[75].

Table 5 Overview of effects of umbilical cord blood-derived mesenchymal stem cells after spinal cord injury

Source of MSC	Main pathological features improved/repaired	Limitations/recommendations/conclusions	Ref.
Human	Stem cells migrated to injured areas, functional recovery	hUCB may be a viable source of stem cells for treatment of neurological disorders	Saporta et al[69], 2003
	Axonal regeneration, functional recovery	HUCBs and BDNF reduced the neurological function deficit to a moderate degree for SCI rats	Kuh et al[70], 2005
	Stem cells secrete neurotrophic hormones and remyelinating proteins, axonal remyelination	Studies on long-term survival of hUCBSC and remyelination are recommended.	Dasari et al[71], 2007
	Repair and maintenance of structural integrity of the injured spinal cord, downregulation of apoptosis, functional recovery	Role of hUCBSC in maintaining structural integrity and thereby promoting the long-term survival of neurons and oligodendrocytes in the injured spinal cord	Dasari et al[72], 2008
	Downregulation of neuronal apoptosis	Modulation of the micro environment of the injured spinal cord by application of hUCBSC might be a potential therapeutic modality	Dasari et al[75], 2009
	Downregulation of elevated tPA activity/expression in SCI rats	tPA is involved in secondary pathogenesis following spinal cord injury	Veeravalli et al[76] 2009
	Upregulation of MMP2, reduction of glial scar	hUCBSC treatment after SCI upregulates MMP-2 levels and reduces the formation of the glial scar	Veeravalli et al[77], 2009
	GDNF and VEGF were secreted in the injured spinal cord after transplantation of CD34+ cells	CD34+ cell therapy may be beneficial in reversing the SCI-induced spinal cord infarction and apoptosis and hindlimb dysfunction	Kao et al[78], 2008
	Serum IL-10 levels increased, TNF-α levels decreased, functional recovery	Recovery of SCI-induced hind limb dysfunction is by increasing serum levels of IL-10, VEGF and GDNF in SCI rats.	Chen et al[79] 2008
	Infarct size and blood vessel density at the injured site were significantly different in the treated group, functional recovery	Transplantation of CD34(+) HUCBCs during acute phase could promote functional recovery better than during subacute phase after SCI by raising blood vessel density	Ning et al[80], 2013

MSC: Mesenchymal stem cell; SCI: Spinal cord injury; IL: Interleukin; TNF-α: Tumor necrosis factor-α; hUCB: Human umbilical cord blood; hUCBSC: Human umbilical cord blood-derived mesenchymal stem cell.

Table 6 Overview of effects of Wharton’s jelly/umbilical cord matrix cells after spinal cord injury

Source of MSC	Main pathological features improved/repaired	Limitations/recommendations/conclusions	Ref.
Human	Survival of transplanted HUMSCs 16 wk, secretion of human neutrophil-activating protein-2, neurotrophin-3, basic fibroblast growth factor, glucocorticoid induced tumor necrosis factor receptor, and vascular endothelial growth factor receptor 3 in the host spinal cord	Transplantation of HUMSCs is beneficial to wound healing after SCI in rats	Yang et al[82], 2008
	Axonal regeneration, neuroprotective action by grafted cells, functional recovery	Co-grafted HUMSCs and BDNF may be a potential therapy for SCI	Zhang et al[83], 2009
	hUCMSCs survive, migrate, and produce GDNF and neurotrophin-3, functional recovery	Studies on dose-dependent effects of hUCMSCs transplantation on SCI are required	Hu et al[84], 2010
	Increased intensity of 5-HT fibers, increased volume of spared myelination, decreased area of cystic cavity, functional recovery	NT-3 enhanced therapeutic effects of HUMSCs after clip injury of the spinal cord.	Shang et al[85], 2011

MSC: Mesenchymal stem cell; SCI: Spinal cord injury; hUCBSC: Human umbilical cord blood-derived mesenchymal stem cell.