Hypoxic culture of umbilical cord mesenchymal stem cell-derived sEVs prompts peripheral nerve injury repair

Abstract

IntroductionRepair and regeneration of the peripheral nerve are important for the treatment of peripheral nerve injury (PNI) caused by mechanical tears, external compression injuries and traction injuries. Pharmacological treatment can promote the proliferation of fibroblasts and Schwann cells (SCs), which longitudinally fill the endoneurial canal and form Bungner’s band, helping the repair of peripheral nerves. Therefore, the development of new drugs for the treatment of PNI has become a top priority in recent years.MethodsHere, we report that small extracellular vesicles (sEVs) produced from umbilical cord mesenchymal stem cells (MSC-sEVs) cultured under hypoxia promote repair and regeneration of the peripheral nerve in PNI and may be a new therapeutic drug candidate.ResultsThe results showed that the amount of secreted sEVs was significantly increased in UC-MSCs compared with control cells after 48 h of culture at 3% oxygen partial pressure in a serum-free culture system. The identified MSC-sEVs could be taken up by SCs in vitro, promoting the growth and migration of SCs. In a spared nerve injury (SNI) mouse model, MSC-sEVs accelerated the recruitment of SCs at the site of PNI and promoted peripheral nerve repair and regeneration. Notably, repair and regeneration in the SNI mouse model were enhanced by treatment with hypoxic cultured UC-MSC-derived sEVs.DiscussionTherefore, we conclude that hypoxic cultured UC-MSC-derived sEVs may be a promising candidate drug for repair and regeneration in PNI.

Stem cell-derived extracellular vesicle-based therapy for nerve injury: A review of the molecular mechanisms

“… 55 Interestingly, Zhu et al found that small extracellular vesicles produced from umbilical cord mesenchymal stem cells cultured under hypoxia accelerated Schwann cells recruitment at the site of nerve injury and enhanced nerve repair and regeneration in a mouse model of sciatic nerve injury; because in the condition of hypoxia, the amount of secreted small extracellular vesicles increases significantly compared to the control cells. 56 …”

Mesenchymal stem cells under epigenetic control – the role of epigenetic machinery in fate decision and functional properties

“…MSCs acquire immunosuppressive functions in a proinflammatory microenvironment (in response to cytokine stimulation such as IL-1α/β, IFNγ, TNF, and IL-17) [ 137 , 138 ], hypoxia conditions [ 139 ], or in response to pharmacological drugs (bortezomib, dexamethasone) [ 140 , 141 ] and chemical/biological agents (LL-37, LPS, curcumin, α-synuclein) [ 142 – 145 ], including epigenetic modifiers (HDAC/DNMT inhibitors) [ 146 , 147 ]. To date, several MSCs mediated immunomodulatory mechanisms have been described, including (1) reduction of T cell-mediated responses by induction of T cell apoptosis, inhibition of T cell proliferation, and supporting of regulatory T cell differentiation [ 148 ]; (2) limitation of B cell responses by regulation B cell proliferation and differentiation towards plasma cells [ 149 ]; (3) inhibition of the cytotoxic function of natural killer (NK) cells [ 150 ]; (4) induction of dendritic cells (DCs) [ 151 ] and monocyte/macrophage (Mo/Ma) tolerogenic properties [ 152 ]; and (5) limitation of inflammatory mediator secretion (Fig.…”