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Subcutaneous Adipose Tissue-Derived Neural Stem Cells Promote Repair of Peripheral Neurotmesis Through Schwann-like Cell Differentiation
Leah C. Ott, Rhian Stavely, Ahmed A. Rahman, Christopher Y. Han, Abigail R. Leavitt, Aki Kashiwagi, Ryo Hotta, Allan M. Goldstein
Department of Pediatric Surgery, Massachusetts General Hospital, Boston, MA
Background: Peripheral nerves (PNs) have the capacity to repair themselves, but functional outcomes remain poor for transection injuries with large gaps. Schwann cells in the subcutaneous adipose tissue (SAT) can adopt neural stem cell (NSC) properties in vitro. Whether SAT-NSCs can engraft and promote regeneration after PN injury is unknown.
Methods: Schwann cells were isolated from SAT of Wnt1-tDTomato reporter mice and cultured in neuroproliferation media, yielding SAT-NSC neurospheres. Adult Plp1-GFP+ pan-glial reporter mice underwent PN injury surgery, in which the left sciatic nerve was sharply transected and repaired with a silicone conduit, creating a 5mm defect. Conduits contained either SAT-NSCs (n=9) or media alone (n=6). Walking track analysis was performed on POD28 and 56 to quantify motor recovery via the sciatic functional index (SFI) score. On POD28 and 56, mice were sacrificed and conduits dissected to assess for nerve repair.
Results: At POD28, SAT-NSCs survived within the conduit and integrated with the regenerating nerve. Nerves demonstrated immunoreactivity to myelin protein zero around host Plp1GFP+ cells and transplanted SAT-NSCs, suggesting both populations participated in myelination. SAT-NSCs also expressed the myelinating Schwann cell marker LGI-1, confirming their Schwann-like cell identity. Mice receiving SAT-NSC-filled conduits compared to media alone demonstrated a significant improvement in SFI by POD56 (mean -84.6 versus -105.9, p=0.042).
Conclusion: Transplanted SAT-NSCs integrate with regenerating PNs and participate in myelination after neurotmesis, differentiating into Schwann-like cells and enhancing distal motor reinnervation. These cells may represent a novel, easily accessible source of autologous NSCs for the treatment of PN injuries.
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