Mesenchymal stem cells’ “garbage bags” at work: Treating radial nerve injury with mesenchymal stem cell-derived exosomes

Table 1 Recently reported peripheral nerve injury repair in the experimental animal models

Ref.	Experimental model (in vitro or animal)	Therapeutic modalities	Main findings
MSCs-based therapy
Zhang et al[4], 2024	SCs from injured sciatic nerves and HUVECs	MSCs treated with PRP-derived exosomes	Treatment with PRP-exosome improved MSC survival. Exosome-treated MSCs, co-cultured with SCs, reduced their apoptosis and enhanced SC proliferation after PNI. Similarly, exosome-treated MSCs also had pro-migratory and angiogenic effects. Cytokine array analysis and ELISA showed upregulation of 155 proteins and downregulation of six proteins, with many pro-angiogenic and neurotrophic factors. Western blot revealed the activation of the PI3K/Akt signaling pathway in exosomes-treated MSCs
Sivanarayanan et al[5], 2023	Sciatic nerve crush injury in rabbit	Allogenic BM-MSCs and their CM	BM-MSCs and BM-MSCS-CM treatment improved the regenerative capacity in acute and subacute injury groups, with slightly better improvements in the subacute groups. BM-MSCs supported the healing process of PNI, whereas CM increased the healing process
Yalçın et al[6], 2023	Sciatic nerve injury in rat	ADSCs	The study documented the role of syndecan-1 and heat shock protein 70 in the regenerative effects of ADSCs on PNI. Histology and EMG showed that treatment with ADSCs significantly improved nerve regeneration and its functionality via the release of nerve growth factor
Liu et al[7], 2020	Sprague-Dawley rats	SC-like ADSCs are placed on an acellular scaffold after treatment with nerve leachate	Sprague-Dawley rats were divided into four groups: Scaffold only, untreated ADSCs + scaffold, nerve leachate-treated ADSCs + scaffold, and autograft. Four months after treatment, the average area, density, and thickness of regenerated nerve fibers in the nerve leachate-treated ADSCs + scaffold group significantly increased compared to the untreated ADSCs + scaffold group. These data show the superiority of nerve leachate-treated ADSCs for treating PNI
Kizilay et al[8], 2017	Wistar rat model of sciatica nerve injury by clip compression	BM-MSCs	The proximal, distal, and mean latency values were higher in MSC treatment groups vs without MSC-treated animals. The nerve conduction velocity, compound action potential, and the number of axons in MSC-treated animals are higher than in non-MSC-treated animals. Also, myelin damage decreased in MSC-treated animals
Cell-free therapy
Growth factor-based approach for PNI
Shi et al[9], 2022	Rat sciatic nerve transection model		In vitro experimental studies show that BDNF/PLGA sustained-release microsphere treatment improved migration and neural differentiation of ADSCs. In vivo studies indicated that BDNF microsphere treatment significantly reduced the nerve conduction velocity compound amplitude compared to the untreated animals. Moreover, the BDNF microsphere group had more closely arranged and uniformly distributed nerve fibers than the control animals
Li et al[10], 2021	Rat sciatic nerve transection model	Leision site injection of a lentivirus expressing FGF13	FGF13 treatment successfully recovered motor and sensory functions via axon elongation and remyelination. FGF13 pretreatment enhanced SCs survival and increased cellular microtubule-associated proteins in vitro PNI model. The data supported the role of FGF13 in stabilizing cellular microtubules, which is essential for promoting PNI repair following PNI
Su et al[11], 2020	Rat sciatic nerve transection model	Composite nerve conduit with slow-release BDNF	The study used fabricated composite nerve conduits with slow-release BDNF to treat PNI and compare the regeneration potentials of autologous nerve grafts. The BDNF composite conduits remained bioactive for at least three months and successfully regenerated a 10-mm sciatic nerve gap
Lu et al[12], 2019	Rat model of sciatic crush injury	Intramuscular delivery of FGF21 once daily for seven days	FGF21 treatment led to functional and morphologic recovery with improved motor and sensory function, enhanced axonal remyelination and re-growth, and increased SC proliferation. Local FGF21 treatment reduced oxidative stress via activation of Nrf-2 and ERK. FGF21 also reduced autophagic cell death in SCs
Exosome-based approach for PNI
Zhu et al[13], 2023	Mouse model of spared nerve injury	Exosomes from UC-MSCs under hypoxia	After 48 h of culture under 3% oxygen in a serum-free culture system, UC-MSCs secreted higher EVs than the control cells. SCs could uptake EVs in vitro and increase their growth and migration. The treatment of animals with EVs accelerated the recruitment of SCs at the PNI site and supported PN repair and regeneration
Hu et al[14], 2023	Rat model of the injured sciatic nerve	SCs-like cells derived from hA-MSCs. Exosomes from hA-MSCs or SC-like cells from hA-MSCs	SC-like cells were successfully differentiated from hA-MSCs and used for exosome collection. Treatment with exosomes from SC-like cells significantly enhanced (vs hA-MSCs-derived exosomes) motor function recovery, reduced gastrocnemius muscle atrophy, and supported axonal regrowth, myelin formation, and angiogenesis in the rat model. They were also more efficiently absorbed by SCs and promoted the proliferation and migration of SCs
Yin et al[15], 2021	In vitro model and a rat model of sciatic nerve injury	ADSCs	Exosome treatment inhibited autophagy and karyopherin-α2 levels, which were significantly increased in SCs in the injured sciatic nerve, both in vivo and in vitro. Abrogation of karyopherin-α2 reduced SCs autophagy, with the role of miRNA-26b. Treatment with exosomes supported myelin sheath regeneration in rats with a sciatic NI
Liu et al[16], 2020	PNI model rats supported by in vitro studies	ADSCs and their derivative exosomes	Treatment with ADSC-derived exosomes significantly reduced SC apoptosis after PNI via increased Bcl-2 and decreased Bax mRNA expression, in addition to increasing SC proliferation. Histological data in PNI model rats also observed these effects
Chen et al[17], 2019	In vitro model and rat sciatic nerve transection model with a 10-mm gap	Human ADSCs-derived exosomes and in vitro	In vitro studies showed that SCs internalized human ASCs-derived exosomes to enhance their proliferation, migration, myelination, and secretion of neurotrophic factors. Treatment with ASC-exosomes supported axon regeneration in a rat sciatic nerve transection model with a 10-mm gap and supported myelination and restoration of denervation muscle atrophy. This data showed the efficacy of exosomes in promoting PN regeneration by restoring SC function
Masgutov et al[18], 2019	Wistar rat sciatic nerve injury model	ADSCs	ADSCs-derived MSCs were delivered using fibrin glue to the traumatic injury, helped to fix the cells at the graft site, and gave extracellular matrix support to the provided cells. The transplanted cells were neuroprotective on DRG L5 sensory neurons and stimulated axon growth and myelination. Also, MSCs promoted nerve angiogenesis and motor function recovery

ADSCs: Adipose-derived mesenchymal stem cells; BM-MSCs: Bone marrow-derived mesenchymal stem cells; BNDF: Brain-derived neurotrophic factor; EVs: Extracellular vesicles; hA-MSCs: Human amniotic-derived mesenchymal stem cells; HUVEC: Human umbilical vein endothelial cells; CM: Conditioned medium; EMG: Electromyography; ERK: Extracellular regulated protein kinases; FGF: Fibroblast growth factor; MSCs: Mesenchymal stem cells; Nrf-2: Nuclear factor erythroid-2-related factor 2; PN: Peripheral nerve; PNI: Peripheral nerve injury; PLGA: Poly(D, L-lactide-co-glycolide; PRP: Platelet-rich plasma; SCs: Schwan cells; UC-MSCs: Umbilical cord mesenchymal stem cells; PI3K: Phosphoinositide 3-kinase.

Table 2 Clinical studies for peripheral nerve injury repair using Schwan cells, stem cells, and their derived exosomes

NCT#	Study title	Conditions	Interventions	Primary outcome	Sponsor	Collaborators
NCT04346680	Intraoperative ADSC administration during nerve release	Neurotmesis of peripheral nerve disorder	ADSC administration	Electrophysiological improvement, improvement in EMG - the appearance of activities in denervated muscles, one year	Mossakowski MRC Polish Academy of Sciences	Centre of Postgraduate Medical Education
NCT03964129	BMAC nerve allograft study	PNI upper limb	Avance nerve graft with autologous BMAC	Comparison of AEs between patients treated with ANG with BMAC and the historical data of nerve repairs with the ANG only. Long-term study - AEs, such as infection, wound dehiscence, neuropathy, carpal tunnel syndrome, bleeding, seroma, and lymphocele, will be recorded and analyzed. AEs will be mapped to a MedDRA-preferred term and system organ classification	Brooke Army Medical Center	Walter Reed National Military Medical Center; Cleveland Clinic Lerner Research Institute
NCT03359330; PKUPH-PNI	Mid-term effect observation of biodegradable conduit small gap tublization repairing PNI	PNIs	Degradable conduit small gap tublization	To observe the mid-term clinical effect of biodegradable conduit small gap tublization on the repair of PNI in multi-center patients and fresh PNIs in the upper extremities	Peking University People’s Hospital	-
NCT05541250	Safety and efficacy of autologous human SCs augmentation in severe peripheral nerve injury	PNIs	Autologous human SC	The primary purpose of this phase I study is to evaluate the safety of injecting one’s SCs along with nerve auto-graft after a severe nerve injury, such as a sciatic nerve or brachial plexus injury	University of Miami, Florida, United States (Recruiting)	-
NCT04654286	Clinical outcomes of HAM and allogeneic MSCs composite augmentation for nerve transfer procedure in brachial plexus injury patients	Brachial plexus neuropathies	Nerve transfer or nerve transfer with HAM-MSC composite wrapping	AROM pre-surgery and 12-month follow-up for shoulder flexion, extension, abduction, adduction, external rotation, and internal rotation using the MRC scale (ranging from 0-5)	Dr. Soetomo General Hospital, Jakarta
Huang et al[19], 2016	A clinical study on the treatment of peripheral nerve injury growth factor of mecobalamin combined with nerve	150 PNI patients	Mecobalamin (0.5 mg, I.V, once a day) combined with NGF (30 mg, I.M injection, once a day) for 3-6 wk	Treatment with mecobalamin combined with NGF improved the sensorimotor evaluation of the curative effect made by the British Medical Research Institute of Neurotrauma Society	Guangxi Basic Science and Technology Plan Project PR China (No.: 20111209)
Civelek et al[20], 2024	Effects of exosomes from mesenchymal stem cells on functional recovery of a patient with total radial nerve injury: A pilot study	One patient with total radial nerve injury	WJ-MSCs derived exosomes	The six-month follow-up based on the BMRC and Mackinnon-Dellon scales showed improved motor (M5, excellent), and sensory functions also showed improvement (S3+, good). These results were achieved without physical therapy. Substantial axonal damage was observed at a ten-week follow-up, but nerve re-innervation was observed by EMG, which also improved significantly during the six-month follow-up	Department of Neurosurgery, University of Health Sciences

ADSCs: Adipose tissue-derived mesenchymal stem cells; AEs: Adverse effects; ANG: Avance nerve graft; AROM: Active range of motion; HAM-MSC: Human amniotic membrane-derived mesenchymal stem cells; BMAC: Bone marrow aspirate concentrate; EMG: Electromyography; MRC: Medical Research Council; MSCs: Mesenchymal stem cells; SCs: Schwan cells; PNI: Peripheral nerve injury; WJ-MSCs: Wharton jelly-derived mesenchymal stem cells; NGF: Nerve growth factor; BMRC: Behavioral Medicine Research Council; ADSC: Adipose-derived stem cell.

Table 3 List some commonly studied growth factors for peripheral nerve injury treatment

Ref.	Growth factor
Sandoval-Castellanos et al[43], 2020	Brain-derived neurotrophic factor
Xu et al[44], 2023	Ciliary neurotrophic factor
Gu et al[45], 2024	Chemokine platelet factor-4
Romano and Bucci[46], 2020	Epidermal growth factor
Cintron-Colon et al[47], 2022	Glial cell line-derived neurotrophic factor
Ye et al[48], 2022	Hepatocyte growth factor
Slavin et al[49], 2021	Insulin-like growth factor-1
Alastra et al[50], 2021	Nerve growth factor
Li et al[51], 2023	NGF+ basic fibroblast growth factor
Golzadeh and Mohammadi[52], 2016	Platelet-derived growth factor
Ding et al[53], 2024	Transforming growth factor
Xu et al[44], 2023	Vascular endothelial growth factor

NGF: Nerve growth factor.