Human umbilical cord derived mesenchymal stem cells in peripheral nerve regeneration

Table 1 Studies of umbilical cord derived mesenchymal stem cells in peripheral nerve axonotmesis and diabetic neuropathy in vivo

Ref.	Study design	Cell source	Subject	Treatment group	Control group	Extraction method	Cell treatment	Delivery method	Follow-up duration (wk)	Results
Hei et al[47], 2016	Case Control	Human	Murine	20 BDNF-transfected UCMSCs; 20 UCMSCs only	20 PBS	Human umbilical vein obtained immediately after delivery	UCMSCs were expanded in keratinocyte-serum free medium with various growth factors. Passage 5 UCMSCs were transfected with adenovirus vector containing BDNF	Xenogenic transplantation into crushed left sciatic nerve	4	Significant improvement in SFI, axon count, axon density, and nerve regeneration in both treated groups. BDNF-loaded UCMSCs showed greater improvements in the above metrics than the UCMSC group
Sung et al[46], 2012	Case Control	Human	Murine	18 UCMSCs	18 PBS	Human umbilical vein obtained immediately after delivery	UCMSCs were culture-expanded in growth factors. Passage 5 UCMSCs were labelled with PKH26 fluorescent cell linker	Xenogenic transplantation into crushed sciatic nerve	4	Significant improvement in SFI, axon density and axon regeneration in UCMSCs group compared to control. Increased BDNF and tyrosine kinase receptor B mRNA compared to control
Gartner et al[48], 2012	Case Control	Human	Murine	6 undifferentiated UCMSCs + PLC; 7 differentiated UCMSCs + PLC; 7 UCMSCs only	6 injury only; 7 injury repaired with PLC only; 6 without injury	UCMSCs from human umbilical cord Wharton’s jelly matrix purchased from third-party source (PromoCell GmbH)	Passage 5 UCMSCs were supplemented with bovine foetal serum. UCMSCs were treated with neurogenic media and differentiated into neuroglial-like cells	Xenogenic transplantation into right sciatic nerve lesion (3 mm) crushed with non-serrated clamp	12	Significant improvement in both undifferentiated and differentiated UCMSCs groups in terms of SFI, EPT, WRL as well as myelin sheath thickness compared to all controls
Gartner et al[49], 2012	Case Control	Human	Murine	6 UCMSCs only; 6 undifferentiated USMSCs + Chitosan type III	6 negative control; 6 wrapped in Chitosan type III	UCMSCs from human umbilical cord Wharton’s jelly matrix purchased from third-party source (PromoCell GmbH)	Passage 5 UCMSCs were loaded on Chitosan type III biomaterial scaffold	Xenogenic transplantation into crushed right sciatic nerve lesion	12	Significant improvement in muscle force deficit and axonal regrowth in UCMSC Chitosan type III group compared to controls
Xia et al[54], 2015	Case Control	Human	Murine	40 UCMSCs	40 saline solution; 40 untreated rats	Human umbilical cord blood plasma obtained from different individuals with identical blood type	UCMSCs were culture-expanded in normal MSC media. Number of passage was not specified	Intravascular injection into left femoral artery of rat with streptozotocin induced diabetic foot ulcer	2	Significant improvement in restoring femoral nerve conduction in UCMSCs group compared to control groups at 3 days, 1 wk and 2 wk

UCMSCs: Umbilical cord derived mesenchymal stem cells; BDNF: Brain-derived neurotrophic factor; SFI: Sciatic function index; PBS: Phosphate buffered saline; PLC: Poly (DL-lactide-ε-caprolactone); WRL: Withdrawal reflex latency; EPT: Extensor postural thrust.

Table 2 Studies of umbilical cord derived mesenchymal stem cells in Peripheral Nerve Neurotmesis in vivo

Ref.	Study Design	Cell Source	Subject	Treatment Group	Control Group	Extraction Method	Cell Treatment	Delivery Method	Follow-up length (wk)	Results
Ma et al[17], 2019	Case Control	Human	Murine	24 UCMSC-extracellular vesicles injections	24 PBS	Human umbilical cords obtained from full-term deliveries	UCMSCs were expanded ex vivo. Passage 3 UCMSCs were used	UCMSC-EV were injected into the tail veins	8	Significant improvement in SFI, axon regeneration, recovery of motor function and reduced muscle atrophy. Regenerated nerve fibre diameter was larger in USMSC-EV injection groups compared to control
Zarbakhsh et al[11], 2015	Case Control	Human	Murine	8 silicone tubes filled with fibrin glue seeded with 500000 UCMSCs	8 silicone tubes filled with fibrin glue seeded with 500000 rat BMMSCs; 8 control rats with nerve gaps filled with fibrin glue	Human umbilical cords obtained from full-term deliveries	Passage 3 UCMSCs were loaded on a 12 mm silicone tube interposed into a 10 mm nerve gap	Xenogenic transplantation into sciatic nerve gap specimens	12	Significant improvement in nerve histomorphology in UCMSC and BMMSC groups compared to controls. BMMSC showed the greater improvement
Cui et al[14], 2018	Case Control	Human	Canine	5 LOCC with UCMSCs	5 negative control; 5 positive control (autografted nerve segment reversed); 5 LOCC only	Human umbilical cords obtained from full-term deliveries.	UCMSCs were expanded. Passage 3 UCMSCs were cultured and embedded into a LOCC	Xenogenic transplantation into transected sciatic nerve of 15 months adult Beagles.	39	Significant improvement in CMAP and conduction latency in LOCC embedded with UCMSC compared to LOCC alone
Pan et al[50], 2017	Case Control	Human	Rabbit	12 NGF loaded HC- scaffold with UCMSCs; 12 HC-scaffold with UCMSCs	12 negative control (no grafting into nerve gap); 12 HC-scaffold with PBS; 12 collagen (C)-scaffold	Human UCMSCs obtained from third party source (Stem Cell Bank of Guangdong Province)	Passage 4 UCMSCs were embedded into NGF- loaded HC-scaffold or C-scaffold	Xenogenic transplantation into transected recurrent laryngeal nerve tissue specimens with daily penicillin injection until day 5 post-intervention	8	Significant improvement in transected nerve repair in UCMSC NGF-loaded HC-scaffold as compared to all other groups
Li et al[53], 2012	Case Control	Human	Murine	40 amnion tube with UCMSCs	40 amnion tube with saline implant	Human umbilical cords obtained from full-term deliveries	Passage 3-4 UCMSCs were cultured and loaded on an amniotic scaffold	Xenogenic transplantation into transected sciatic nerve tissue specimens	20	Significant improvement in SFI and CMAP in UCMSC group compared to control. Gradual improvement in threshold stimulus and maximum stimulus intensity in UCMSC group compared to control
Li et al[6], 2013	Case Control	Human	Human	12 neurolysis followed by 10 mL UCMSCs injection of 1.75 × 107 cells	20 neurolysis only	Human umbilical cords obtained from full-term deliveries	Passage 2 UCMSCs were loaded on an amniotic membrane scaffold. Both groups received 3 days of oral cephalosporin	Allogenic transplantation into radial nerve injury following radial shaft fracture	12	Significant improvement in muscular strength, touch and pain sensations in UCMSC group compared to control. Improved electrophysiological function in UCMSC group as compared to control
Matsuse et al[35], 2010	Case Control	Human	Murine	6 UCMSCs; 10 Induced UCMSC	6 negative control; 5 induced UCMSC	Wharton’s Jelly extracted from umbilical cords of full-term caesarean deliveries	Passage 3 UCMSCs were induced into Schwann-like cells	Xenogenic transplantation into transected sciatic nerve tissue specimens.	3	Significant improvement in SFI in all treated as compared to control with the greatest improvement in UCMSC group
Xiao et al[51], 2015	Case Control	Human	Rabbit	10 chitosan conduit anastomosis bridge filled with UCMSCs	10 chitosan conduit anastomosis only; 10 untreated	Not specified	UCMSCs were loaded into a chitosan conduit	Xenogenic transplantation into tibial-common peroneal nerve end-to-side anastomosis	12	Significant improvement in myelin sheath thickness, Schwann cell growth, growth of axis bud and growth velocity of regenerated fibre in UCMSC group compared to controls. No significant difference observed between either control groups
Pereira et al[52], 2014	Case Control	Human	Murine	6 undifferentiated UCMSCs + PLC; 6 differentiated UCMSCs into neural-glial-like cells + PLC	6 untreated; 6 treated with suture; 6 without nerve gap	Human Wharton’s Jelly UCMSCs obtained from third-party source (PromoCell GmbH)	Passage 5 UCMSCs were fixed onto PLC scaffold	Xenogenic transplantation into sciatic nerve gap specimens	20	Both UCMSC treated groups showed increased myelin sheath thickness, enhanced recovery in motor and sensory function. No significant difference was noted between differentiated and undifferentiated groups. PLC use did not significantly improve nerve regeneration

UCMSCs: Umbilical cord derived mesenchymal stem cells; LOCC: Longitudinally orientated collagen conduit; SFI: Sciatic function index; NGF: Nerve growth factor; PBS: Phosphate buffered saline; HC: Heparinized collagen; PLC: Poly (DL-lactide-ε-caprolactone); EV: Extracellular vesicle.