Plastic Surgery Research Council

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Schwann Cell-like Cells (iMDSC) Differentiated from Muscle-Derived Stem Cells (MDSC) Improve Neuromuscular Re-innervation and Functional Outcomes After Rodent Upper Extremity Peripheral Nerve Trauma
Joseph Lopez, MD, Helen Xun, BS, Pooja Yesantharao, BS, MS, Leila Musavi, BS, Kim X. Sinan, BS, Howard D. Wang, MD, Amy Quan, MD, Markus Tammia, Ph.D, Aysel Cetinkaya-Fisgin, Ph.D, Ahmet Hoke, MD Ph.D, Gerald Brendacher, MD, WP Andrew Lee, MD, Anand Kumar, MD.
Johns Hopkins School of Medicine, Baltimore, MD, USA.

Purpose: Peripheral nerve injuries are common and have debilitating effects, including loss of nerve and muscle function, painful neuropathies, and impaired sensation. Current therapies do not address a major challenge of peripheral nerve regeneration: the atrophy or loss of Schwann cells (SC), which are the principal glia cell that support peripheral neurons. Recent interest in peripheral nerve regeneration has focused on using stem-cell derived SC for cellular replacement therapy. Mesenchymal stem cells, including adipose and bone marrow, have been proposed to be a good source of SC. However, bone marrow biopsies are invasive, and adipose-derived stem cells have been shown to rapidly dedifferentiate in the absence of stimulating media. Consequently, there is a pressing need to identify alternative mesenchymal stem cell sources for SC cellular replacement therapy to improve peripheral nerve regeneration. The purpose of this study was to assess the impact of muscle-derived stem cells (MDSCs) in augmenting nerve regeneration and improving muscle function after nerve trauma.  
Methods: Our lab derived SC-like cells from GFP+ muscle-derived stem cells (GFP+ MDSCs) to investigate the potential of SC replacement therapy in the promotion of peripheral nerve regeneration. To assess the in-vivo effects of GFP+  MDSC-derived SC-like cells (GFP+ iMDSC) on peripheral nerve regeneration, we used a median nerve injury model developed in our laboratory. Four groups (n=5 per group) of rats with median nerve injuries were examined: (1) Group-1 animals were treated with intraneural PBS after nerve trauma (negative control); (2) Group-2 were naive controls; (3) Group-3 animals were treated with intraneural GFP+ MDSCs; (3) Group-4 animals were treated with GFP+ iMDSCs. All animals underwent weekly upper extremity functional testing.  Five weeks post-treatment, the rats were sacrificed, and the median nerve and extrinsic finger flexor muscles were harvested for nerve histomorphometry, nerve myelination, muscle weight & atrophy, GFP+ MDSC engraftment and proliferation, and neuromuscular re-innervation analyses.
Results: Immunofluorescence studies of the median nerve demonstrate that GFP+ iMDSC remain stably transformed in-vivo 5 weeks post injection, and localize in the endoneurium of the median nerve. GFP+ iMDSC were found to co-express S100 (SC cell surface marker) and Ki-67 (a cellular proliferation marker) in vivo. Median nerve regeneration was higher in iMDSC-treated animals when compared to untreated controls (G-ratio: group 1 [0.47]  vs group 4 [0.512] , p = 0.2195), though this was not statistically significant. iMDSC therapy improved muscle re-innervation (p = 0.033), and decreased muscle atrophy (p = 0.0143). Lastly, iMDSC-treated animals demonstrated greater functional muscle recovery when compared to untreated control (hand grip: group-1 [0.91 N] vs group-4 [3.38 N], p < 0.0001) at five-weeks post-treatment.
Conclusions:
Schwann-Cell like cells (iMDSCs) derived from muscle mesenchymal stem cells decrease denervation muscle atrophy and improve neuromuscular re-innervation, and subsequent functional outcomes after upper extremity nerve trauma in rodents.


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