Table 1.
Summary of current evidence assessing the efficacy of different types of stem cell on peripheral nerve regeneration
| Stem cell source | Author | Experimental model | Stem cell Diff. | Scaffold | Delivery system | Outcome |
| Embryonic | Cui et al[71] | Rat sciatic transection (10 mm gap) | D | Culture medium | Epineurium natural conduit | Cell survival and differentiation into SCs after 3-mo; superior regeneration of myelinated axons in comparison to culture media alone |
| Lee et al[75] | Mouse sciatic transection (2 mm gap) | U | Matrigel | Direct injection of microspheres | ESC-derived MSC sphere-treated nerves recovered significantly greater CMAP, SFI and histological parameters than ESC-MSC single cell suspension | |
| Kubo et al[77] | Mouse tibial | D | PBS | Direct injection into gastrocnemius muscles following nerve transection and repair | Co-culture identified formation of new NMJs; muscle transplanted with stem cells experienced less atrophy 7 and 21-d post injury; cells transplanted after 2-wk were unable to provide any protective effect; motor recovery following repair superior in those muscles receiving stem cells | |
| Craff et al[76] | Rat sciatic + gastrocnemius muscle | D | PBS | Direct injection into gastrocnemius muscles following nerve transection | Muscles injected with stem cells retained muscle weight preservation and myocyte cross sectional area in comparison to control muscle after 7-d post injury. New NMJs observed. Benefits lost after 21 d | |
| Neural | Fu et al[15] | Rat sciatic transection (15 mm gap; gene transfection) | U (gene therapy) | Culture medium (cells seeded directly onto conduit wall) | Poly(D,L-Lactide) conduit | Enhanced expression of BDGF and GDNF in transfected cells; conduits with transfected cells led to larger myelinated axons and improved functional and electrophysiological outcome |
| Zhang et al[62] | Rabbit facial nerve transection (5 mm gap) | U | Collagen medium | HA-collagen composite conduit | Conduits with NSCs and NT-3 experienced superior outcomes in comparison to NSC alone; results equivalent to normal nerves after 12-wk | |
| Murakami et al[86] | Rat sciatic transection (15 mm gap) | U | Collagen gel | Silicone conduit | NSCs differentiated into astrocytes, oligodendrocytes and schwann cell-like cells; dNCSs implanted into 15 mm defects; Improved axon number, diameter and myelination compared with controls; labeled cells present after 10-wk; expressed markers of SC phenotype | |
| Guo et al[87] | Rabbit facial nerve transection (10 mm gap) | U | Collagen sponge | Chitosan conduit | Electrophysiological and histological outcomes and immunohistochemistry superior in chitosan conduits seeded with NSCs and NGF in comparison to conduit+NGF alone. Results comparable to standard autograft | |
| Liard et al[88] | Pig nervis cruralis transection (30 mm gap) | U | Neurosphere in culture medium | Autologous vein graft | Grafts containing NSCs recovered superior EMG recording and immunohistochemistry profiles in comparison to empty conduits; NSCs identifiable after 240 d follow-up. | |
| Johnson et al[89] | Rat sciatic crush, transection, (10 mm gap) | U (C17.2) | Culture medium | Direct injection | 12/45 rodents developed neuroblastomas | |
| Bone marrow | Zhao et al[160] | Rat sciatic transection (15 mm gap) | U | Fibrin glue | ANA | Survival of BMSCs within fibrin glue; growth factor secretion preserved (NGF, BDNF); equivalent results when cells injected directly into nerve compared with around nerve |
| Hu et al[165] | Monkey median transection (50 mm gap) | U | Culture medium | Chitosan conduit with longitudinally aligned PGLA fibers | Functional and electrophysiological recovery and FG retrograde tracing after 1-year with BMSC-laden conduits equivalent to autograft and superior to empty conduits | |
| Dezawa et al[19] | Rat sciatic transection (15 mm gap) | U + D | Matrigel | Matrigel graft | Successful differentiation into SC phenotype; Axon number and elongation superior with dBMSCs | |
| Jia et al[32] | Rat sciatic transection (10 mm gap) | U | Gelatin | Acellular xenograft | Neurotrophic factor expression elevated in BMSC xenografts; regeneration and functional recovery significantly better than empty xenografts and equivalent to autograft | |
| Mohammadi et al[34] | Rat sciatic transection (10 mm gap) | U | Culture medium | Vein graft | Veins filled with uBMSCs had significantly improved functional, histological and immunohistochemical outcomes compared with veins filled with PBS | |
| Nijhuis et al[36] | Rat sciatic transection (15 mm gap) | U | Culture medium | Vein graft +/- muscle | BMSC identifiable after 6 and 12-wk follow-up; vein graft + muscle + BMSCs outperformed vein graft+muscle but inferior to autograft | |
| Salomone et al[39] | Rat facial nerve transection (3 mm gap) | U + D | Matrigel | Silicone conduit | Histological outcomes superior in conduits containing uBMSCs and dBMSCs compared to empty and matrigel containing conduits; functional outcomes superior using uBMSCs | |
| Wang et al[41] | Rat sciatic transection (15 mm gap) | U | Culture medium | Direct injection into ANA | BMSC produced NGF and BDNF; CSPGs reduced in grafts treated with ChABC Allograft containing BMSCs and ChABC resulted in superior functional, electrophysiological and histological outcome compared with BMSC alone | |
| Adipose | di Summa et al[28] | Rat sciatic transection (10 mm gap) | D | Culture medium | Fibrin glue conduit | Reduced muscle atrophy in autograft, dADSC and dBMSC groups in comparison to empty conduits; dADSCs recovered greatest axon and fiber diameter, evoked potentials and regeneration of motorneurons; results comparable to autograft |
| Tomita et al[21] | Rat common peroneal nerve transection (no gap) | D | Culture medium | Direct injection into distal nerve | dADSCs survived for at least 10 wk in vivo; dADSCs associated with axons and participated in re-myelination; dADSCs resulted in regeneration superior to cultured SCs | |
| Zhang et al[31] | Rat sciatic transection (10 mm gap) | D | Collagen gel | Xenogeneic acellular graft | dADSCs formed columns resembling bands of Büngner and expressed NGF, BDNF and GDNF; axon regeneration, retrograde labeling and electrophysiology were similar between dADSCs and SC supplemented grafts, superior to empty grafts but inferior to standard autograft | |
| Mohammadi et al[33] | Rat sciatic transection (10 mm gap) | U | Culture medium | Vein graft | No difference in functional, morphometric or immunohistochemistry between ADSCs and BMSCs | |
| Erba et al[45] | Rat sciatic transection (10 mm gap) | U | Fibrin | PHB conduit | Lack of sufficient quantities of viable cells 14-d after transplantation; conclusion that regenerative effect due to initial growth factor boost or paracrine effect on resident cells | |
| Sun et al[51] | Rat facial transection (8 mm gap) | D | Matrigel | Decellularized allogeneic artery | dADSCs persisted at repair site and integrated with regenerated tissue; conduits containing dADSCs achieved results comparable to those of SC-containing conduits and superior to matrigel-containing conduits alone; results inferior to autograft | |
| Fetal | Pan et al[106] | Rat sciatic crush | U | Fibrin glue | Direct injection at site | High expression of BDNF, CNTF, NGF and NT-3 found in AFMSCs; motor function, CMAP and conduction velocity improved in those nerves augmented with AFMSCs; high levels of S-100 and GFAP and reduced fibrosis found at repair site |
| Pan et al[111] | Rat sciatic crush | U | Fibrin glue | Direct injection at site | HBO therapy reduced production of inflammatory cytokines and macrophage chemokines following crush injury; when administered with AFMSCs, HBO reduced apoptosis of AFMSCs in comparison to AFMSCs alone; myelination and motor recovery superior in HBO + AFMSC group | |
| Pan et al[110] | Rat sciatic crush | U | Fibrin glue | Direct injection at site | Anti-apoptotic, anti-inflammatory agent G-CSF, when administered with AFMSCs, reduced crush-induced inflammation, and apoptosis in comparison to AFMSCs alone; myelination and motor function superior with AFMSCs + G-CSF in comparison to AFMSCs alone | |
| Matsuse et al[109] | Rat sciatic nerve transection (8 mm gap) | U + D | Matrigel | “Transpermeable” tube | Differentiated UC-MSCs regenerated greater number of myelinated axons and thicker nerve fibers compared with undifferentiated UC-MSCs; number of labeled cells greater in dUC-MSC nerves; results comparable to SC group | |
| Cheng et al[113] | Rat sciatic crush | U | Matrigel | Direct injection at site | AFMSCs successfully transfected; high expression of GDNF detected for 4 wk before subsiding; GDNF-modified AFMSCs recovered greatest SFI, conduction velocity, CMAP and muscle weight in comparison to AFMSCs alone | |
| Gärtner et al[108] | Rat sciatic crush | D | Culture medium | Cells seeded onto PLC wrap | Wraps seeded with UC-MSCs resulted in superior increased myelin thickness, motor and sensory function in comparison to unseeded wraps | |
| Skin | McKenzie et al[120] | Mouse sciatic crush | D/U | Culture medium | Direct injection at site | SKPs successfully induced into SKP-SCs; SKP and SKP-SCs associated with and myelinated axons |
| Marchesi et al[123] | Rat sciatic transection (16 mm gap) | D | PBS | (1) Synthetic co-polymer L-lactide and trimethylene carbonate; and (2) collagen conduit | SFI and CMAPs were significantly better in conduits filled with SDSCs; number of regenerated myelinated axons significantly greater in SDSC conduits; no significant difference in neurotrophic factor expression | |
| Walsh et al[124] | Rat sciatic transection (12 mm gap) | D | Culture medium | Direct injection into acellular freeze-thawed nerve graft | SKP-SCs maintained differentiation up to 8-wk; outcomes significantly improved in comparison to cell free grafts and comparable to cultured SCs; neurotrophic factor release greater in SKP-SCs | |
| Walsh et al[121] | Rat CP/tibial (Immediate vs chronic repair; no gap) | D | Culture medium | Direct injection into distal nerve | Muscle weight and CMAPs superior in SKP-SC group in comparison to media injected controls; significantly higher counts of axon regeneration in SKP-SC group equivalent to immediate suture group | |
| Walsh et al[22] | Rat sciatic transection [acute vs chronic vs ANA (12 mm gap)] | U/D | Culture medium | Direct injection into nerve ends and ANA | SKP-SCs maintained in vivo viability and differentiation better than uSKP; viability poorest in normal nerve, best in acutely injured nerve; SKP-SCs remain differentiated over time and myelinate axons; neuregulin able to prevent apoptosis following transplantation | |
| Khuong et al[122] | Rat sciatic and tibial (12 mm gap) | D | Culture medium | Direct injection into ANA | SKP-SCs containing allografts resulted in superior functional and histological outcomes in both acute and delayed injury models compared with SCs and media controls | |
| Hair follicle | Amoh et al[135] | Mouse sciatic and tibial transection (no gap) | U | Culture medium | Direct injection at site | HFSC transplanted nerves recovered significantly greater function compared with untreated nerves; GFP-labeled cells differentiated into GFAP positive schwann cells and were involved with myelination |
| Amoh et al[133] | Mouse sciatic crush | U | Culture medium | Direct injection at site | HFSCs transplanted around crushed nerve differentiated into SC-like cells and participated in myelination; gastrocnemius muscle contraction significantly greater compared with untreated crushed nerves | |
| Amoh et al[134] | Mouse sciatic transection (2 mm gap) | U | Culture medium | Direct injection at site | HFSCs differentiated into GFAP expressing SCs and were able to myelinate axons; gastrocnemius muscle contraction significantly greater compared with untreated nerves | |
| Lin et al[136] | Rat sciatic transection (40 mm gap) | D | PBS | Direct injection into acellular xenograft | Differentiation into neurons and SCs maintained for 52-wk; number of regenerated axons, myelin thickness and ratio of myelinated axons to total nerve count significantly higher in dHFSCs compared with acellular grafts; conduction velocity slower in dHFSC nerves | |
| Induced pluripotent stem cell | Ikeda et al[146] | Mouse sciatic nerve (5 mm gap) | D | Microsphere seeded into conduit | Mixed PLA/PCL conduit +/- iPSC microspheres +/- bFGF | Regeneration was accelerated by combination of iPSCs + bFGF within conduits in comparison to iPSCs and bFGF alone; outcomes remained inferior to autograft controls; empty conduits performed least well |
| Uemura et al[148] | Mouse sciatic nerve (5 mm gap) | D | Microsphere seeded into conduit | Mixed PLA/PCL conduit +/- iPSC microspheres | Motor and sensory recovery was superior in iPSC group at 4, 8 and 12 wk in comparison to empty conduits. Axonal regeneration superior in iPSC group. Conduit structurally stable after 12 wk | |
| Wang et al[149] | Rat sciatic nerve (12 mm gap) | D | Matrigel | PLCL/PPG/sodium acetate copolymer electrospun nanofiber conduit | Conduits filled with either (1) matrigel; (2) matrigel + NCSCs differentiated from ESCs; and (3) matrigel + NCSCs differentiated from iPSCs; NCSC differentiated into SCs and integrated into myelin sheaths; electrophysiology and histology showed equivalent regeneration in all NCSC containing conduits; no teratoma formation observed after 1-yr |
ADSC: Adipose derived stem cell; ANA: Acellular nerve allograft; AFMSC: Amniotic fluid derived mesenchymal stem cell; BDNF: Brain derived neurotrophic factor; BDGF: Brain derived growth factor; bFGF: Basic fibroblast growth factor; BMSC: Bone marrow derived mesenchymal stem cell; CP: Common peroneal; CMAP: Compound muscle action potential; CSPG: Chondroitin sulphate proteoglycan; ChABC: Chondroitinase ABC; D: Differentiated; DMEM: Dulbecco’s Modified Eagle’s Medium; ECM: Extracellular matrix; EMG: Electromyography; ESC: Embryonic stem cell; FG: Fluorogold; GFAP: Glial fibrillary acidic protein; GDNF: Glial cell derived neurotrophic factor; G-CSF: Granulocyte colony stimulating factor; GFP: Green fluorescent protein; HA: Hyaluronic acid; HFSC: Human fetal derived stem cell; HBO: Hyperbaric oxygen; iPSC: Induced pluripotent stem cell; MSC: Mesenchymal stem cell; NCSC: Neural crest stem cell; NGF: Nerve growth factor; NMJ: Neuromuscular junction; NSC: Nerve stem cell; NT-3: Neurotrophin-3; PBS: Phosphate buffered saline; PCL: Poly-ε-caprolactone; PFTE: Polytetrafluoroethylene; PGLA: Polyglycolic lactic acid; PHB: Polyhydroxybutyrate; PLA: Poly-L-lactide; PLCL: Poly(L-lactide-co-caprolactone); PPG: Polypropylene glycol; SC: Schwann cell; SFI: Sciatic function index; SKP: Skin derived precursor; SKP-SC: Skin precursor derived Schwann cell; SDSC: Skin derived stem cell; U: Undifferentiated; USW: Ultra-short wave therapy.