Mesenchymal stem cell-based therapy for peripheral nerve injuries: A promise or reality?

Table 1 Summary of the Seddon[23] and Sunderland[24] classification of peripheral nerve injury

Classification
Seddon	Neuropraxia	Axonotmesis	Axonotmesis	Axonotmesis	Neurotmesis
Sunderland	I	II	III	IV	V
Injury	Focal demyelination	Axon and myelin damage	Axon, myelin and endoneurium damaged	Axon, myelin, endoneurium, and perineurium damaged	Complete nerve transection
Spontaneous recovery	Yes. Hours to a few weeks	Yes. Weeks to months	Not probable	Highly improbable	Spontaneous functional recovery is not possible
Surgical intervention	Normally not	Normally not	May be necessary	Necessary	Necessary

Adapted from Hussain et al[25] and Maugeri et al[26].

Table 2 Transplantation of mesenchymal stem cells in peripheral nerve injuries

Cell	Delivery	Models	Cell numbers	Outcome	Notes	Ref.
AT-MSCs (canine)	Perineural	Rat sciatic nerve crush	1 × 106	Improved electrophysiological and motor recovery	Assessment performed for 4 weeks	[83]
AT-MSCs (rat)	Intraperitoneal	Rat sciatic nerve transection and suture repair	2 × 106	Improvement in nerve regeneration and functionality	No difference was observed in compound muscle action potential latency between the saline and MSC groups	[81]
BM-MSCs (rat)	IM and IV	Small gap neurorrhaphy (rat sciatic nerve)	1 × 106	Improvements in the sciatic function index, nerve conduction velocity, and myelin sheath thickness	The IM group showed better results compared with the IV group	[80]
BM-MSCs (rat)	IV and epineural	Rat sciatic nerve transection and suture repair	IV: 1 × 106. Epineural: 5 × 104	Enhancement in the recovery rate of compound muscle action potential amplitudes and axon counts	IV administration showed a more pronounced effect on electromotor recovery, while epineural injection was more effective in increasing fiber counts	[82]
BM-MSCs (rat)	Local injection and IV	Rat sciatic nerve transection/repair and individual nerve transection/repair	5 × 106	Improvements in motor function recovery in both models	The motor function recovery was significantly more pronounced in the individual nerve transection/repair model compared with the sciatic nerve transection/repair model	[85]
BM-MSCs (rat)	Subepineural	Rat sciatic nerve transection and surgical coaptation	5 × 105	Improvements in the sciatic function index	The group treated with MSCs and immunomodulators had better functional recovery than the group treated with MSCs alone. Immunomodulation using LPS and FK506 can improve MSC survival after transplantation	[84]

AT-MSCs: Adipose tissue-derived mesenchymal stem cells; BM-MSCs: Bone marrow-derived mesenchymal stem cells; MSCs: Mesenchymal stem cells; IM: Intramuscular; IV: Intravenous; LPS: Lipopolysaccharide.

Table 3 Combination of mesenchymal stem cells and nerve guidance conduits for the treatment of peripheral nerve injuries

Cell source	Conduits	Models	Cell numbers	Outcome	Notes	Ref.
AT-MSCs (human)	Polycaprolactone	15 mm gap in the rat sciatic nerve	1 × 106	Improvement in axonal growth and expression of factors that aid in reinnervating muscle tissue	Poloxamer hydrogel + AT-MSCs promote more axonal growth than when AT-MSCs were delivered without it	[97]
AT-MSCs (rat)	Fibrin gel	A 20 mm segment of the sciatic nerve was excised in rats and sutured back in the reverse direction	3 × 106	Enhanced remyelination, axonal regeneration, and functional recovery	The use of AT-MSCs resulted in a significant improvement compared with the autologous nerve graft group	[98]
AT-MSCs (rat)	Silicone tube	10 mm gap in the rat sciatic nerve	1 × 106	Improvement in the recovery of walking function	The combination of AT-MSCs with platelet-rich fibrin showed better results than AT-MSCs alone	[99]
AT-MSCs (canine)	Polycaprolactone + heterologous fibrin biopolymer	12 mm gap in the rat sciatic nerve	1 × 106	Improvement in functional motors and electrophysiological recovery	The improvements observed were not significantly different from those obtained with autografts	[100]
AT-MSCs (rat)	Chitosan + acellular nerve	10 mm gap in the rat sciatic nerve	Unknown	Improvement in neurological and motor function and in the quality of the myelin sheath	At 12 weeks there was no significant difference in the degree of recovery compared with the autograft group. The electrophysiological characteristics were also similar to those of the autograft	[101]
BM-MSCs (rat)	Polycaprolactone + fibrin sealant	6-7 mm gap in the rat sciatic nerve	3 × 105	Improvement in the regeneration process, modulation of SCs, and motor functional recovery	There was no significant difference in the total estimated number of regenerated fibers between the groups	[102]
BM-MSCs (rat)	Bio 3D conduits from BM-MSCs	5 mm gap in the rat sciatic nerve	3 × 105	Improvements in nerve regeneration, kinematic analysis, and morphological parameters	No neuroma formation was found 8 weeks after the surgery. The Bio 3D group exhibited a higher abundance of myelinated axons compared with both the silicone NGC group and the silicone NGC with MSCs group	[96]
UC-MSCs (human)	Longitudinally oriented collagen conduit	A 35-mm-long segment of the dog’s sciatic nerve was removed	1 × 106	Improvements in axonal regeneration and functional recovery	Nerve regeneration was inferior to the autologous nerve graft group	[103]
UC-MSCs (human)	Bio 3D conduits from UC-MSCs	5 mm gap in the rat sciatic nerve	3 × 105	Improvements in kinematic analysis, as well as in the diameters and number of myelinated axons	The Bio 3D conduit showed better results than the silicone tube and demonstrated nerve regeneration comparable with the autologous group. UC-MSCs in the Bio 3D conduit gradually diminished until week 8	[95]
WJ-MSCs (human)	Acellular nerve	10 mm gap in the rat sciatic nerve	1 × 106	Improvements in myelin and axon regeneration, nerve function, and muscle atrophy reduction	Evaluation at 8 weeks. Increased in both the proportion of myelin in the tissue and myelin thickness, resembling the results seen in the autograft group	[104]
WJ-MSCs (human)	Poly (DL-lactide-e-caprolactone) copolyester	10 mm gap in the rat sciatic nerve	2 × 106	Improvements in nerve regeneration, functional recovery, and increased expression of neurotrophic and angiogenic factors	Evaluation at 12 weeks	[105]
OM-MSCs (rat)	Chitosan	About 10 mm gap in the rat sciatic nerve	1 × 106	Improved in nerve regeneration, motor performance, sciatic indexes, and lower gait dysfunction	The treated groups did not show a significant difference in the stereological results	[106]
GMSCs (human)	Bio 3D conduits from GMSCs	A 5 mm gap in the buccal branch of the rat facial nerve	4 × 104	Improvements in nerve regeneration and functional recovery	Effects comparable to the autograft group	[94]

AT-MSCs: Adipose tissue-derived mesenchymal stem cells; BM-MSCs: Bone marrow-derived mesenchymal stem cells; UC-MSCs: Umbilical cord-derived mesenchymal stem cells; WJ-MSCs: Wharton’s jelly-derived mesenchymal stem cells; OM-MSCs: Olfactory mucosa-derived mesenchymal stem cells; GMSCs: Gingiva-derived mesenchymal stem cells; NGC: Nerve guidance conduit; SCs: Schwann cells; 3D: Three-dimensional.

Table 4 Transplantation of Schwann-like cell-derived mesenchymal stem cells in peripheral nerve injuries

Starting cell	Delivery	Models	Method of transdifferentiation	Cell numbers	Effects	Notes	Ref.
AT-MSCs (rat)	Nerve fibrin conduit	10 mm gap in the rat sciatic nerve	Chemical and growth factors	2 × 106	Improvement in axonal regeneration	No undifferentiated MSC transplantation group. Similar outcomes were observed between the SLCs derived from AT-MSCs and BM-MSCs 2 weeks post-transplantation	[125]
AT-MSCs (rat)	Nerve fibrin conduit	10 mm gap in the rat sciatic nerve	Chemical and growth factors	2 × 106	Improvement in axonal and fiber diameters and reduction in muscle atrophy (gastrocnemius)	No undifferentiated MSC transplantation group. SLCs derived from AT-MSCs were more effective than those derived from BM-MSCs after 4 months	[126]
AT-MSCs (rat)	Silicone tube	10 mm gap in the rat sciatic nerve	Chemical and growth factors	1 × 106	Improvement in axonal regeneration, sciatic function index, and myelination	AT-MSCs and SLCs exhibited a similar impact on nerve regeneration 6 months post-transplantation	[127]
AT-MSCs (human)	Local injection	Tibial crush in rats	Chemical and growth factors	1 × 105	Improvement of survival and myelin formation rates	AT-MSCs secreted neurotrophic factors, though in lower quantities compared with SLCs, and expressed glial markers p75 and GFAP even without stimulation	[128]
AT-MSCs (rat)	NeuraWrapTM sheath	15 mm gap in the rat sciatic nerve	Chemical and growth factors	4 × 106	Improvement in axonal regeneration and myelination. The conduits containing SLCs resulted in a 3.5-fold greater proportion of axons in the distal nerve stump compared with the empty conduits after 8 weeks	No undifferentiated MSC transplantation group	[129]
AT-MSCs (rat)	Silicone tube	7 mm gap in the rat facial nerve	Chemical and growth factors	1 × 105	Improvement in axonal regeneration and in the functional recovery of the facial nerve	AT-MSCs, SLCs, and SCs showed similar nerve regeneration potential after 13 weeks	[130]
AT-MSCs (ovine)	Acellular nerve allograft	30 mm gap in the ovine peroneal nerve	Chemical and growth factors	3 × 105	Improvement in hindlimb function, motor recovery, and remyelination	The autograft showed better organization of the myelin sheaths and axons than acellular nerve allografts recellularized with SLCs after 12 months	[131]
AT-MSCs (ovine)	Acellular xenografts (human)	20 mm gap in the ovine sciatic nerve	Chemical and growth factors	3 × 105	Improvement in metatarsus mobility and strength. Presence of several intrafascicular axons at the graft extremes	No difference was observed between the allograft and xenograft recellularized with SLCs groups in the biceps femoris and gastrocnemius electromyographic response after 6 months	[132]
BM-MSCs (rat)	Hollow fiber	12 mm gap in the rat sciatic nerve	Chemical and growth factors	1-2 × 107	Motor nerve conduction velocity and sciatic nerve function improved significantly. There was an increase in the number of regenerated axons	No tumor formation was observed in the graft or the sciatic nerve segment after 6 months	[133]
BM-MSCs (human)	Transpermeable tube	10 mm gap in the rat sciatic nerve	Chemical and growth factors	1-2 × 107	Increase in the number of regenerated axons and improvement in the sciatic function index	Intraperitoneal administration of FK506 as an immunosuppressant during the 3 weeks of evaluation	[134]
BM-MSCs (rat)	Chitosan conduit	12 mm gap in the rat sciatic nerve	Induction of neurospheres, exposure to growth factors, and co-culture	1.5 × 105	Enhanced axonal repair and remyelination	The nerve repair and functional recovery were similar to those from sciatic nerve-derived SCs	[135]
BM-MSCs (rabbit)	Autogenous vein	10 mm gap in the rabbit facial nerve buccal branch	Chemical and growth factors	2 × 105	Improvement in axon regeneration and remyelination	SLC group provided a faster rate of axonal extension and a larger area of myelination than the BM-MSCs group	[136]
BM-MSCs (human)	Chitosan conduit	12 mm gap in the rat sciatic nerve	Induction of neurospheres, exposure to growth factors, and co-culture	1.5 × 105	Enhanced axonal regeneration and myelination	Subcutaneous administration of cyclosporin A for immunosuppression	[137]
WJ-MSCs (human)	Transpermeable tube	8 mm gap in the rat sciatic nerve	Chemical and growth factors	1-2 × 107	Improvement in axonal regeneration and functional recovery	No tumor formation was observed after 3 weeks. The ability of SLCs to promote axonal regeneration was similar to that of human SCs, as evidenced by functional recovery and histological evaluation. Subcutaneous administration of FK506 for immunosuppression	[138]
UCB-MSCs (human)	3D-cell spheroids	Sciatic nerve crush in rats	Chemical and growth factors	5 × 105	Improvement in functional and structural recovery	Subcutaneous administration of cyclosporin A for immunosuppression	[139]
GMSCs (human)	3D-collagen hydrogel	Sciatic nerve crush in rats	Encapsulation in the methacrylated 3D-collagen hydrogel	2 × 106	Improvement in axonal regeneration and functional recovery	SLCs demonstrated immunomodulatory activity, reducing M1 macrophage activation and promoting M2 macrophage polarization	[120]

AT-MSCs: Adipose tissue-derived mesenchymal stem cells; BM-MSCs: Bone marrow-derived mesenchymal stem cells; GFAP: Glial fibrillary acidic protein; GMSCs: Gingiva-derived mesenchymal stem cells; MSC: Mesenchymal stem cell; SCs: Schwann cells; SLCs: Schwann-like cells; UCB-MSCs: Umbilical cord blood-derived mesenchymal stem cells; WJ-MSCs: Wharton’s jelly-derived mesenchymal stem cells; 3D: Three-dimensional.