Human muscle–derived stem/progenitor cells promote functional murine peripheral nerve regeneration
Mitra Lavasani, … , Bruno Péault, Johnny Huard
Mitra Lavasani, … , Bruno Péault, Johnny Huard
Published March 18, 2014
Citation Information: J Clin Invest. 2014;124(4):1745-1756. https://doi.org/10.1172/JCI44071.
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Research Article

Human muscle–derived stem/progenitor cells promote functional murine peripheral nerve regeneration

Abstract

Peripheral nerve injuries and neuropathies lead to profound functional deficits. Here, we have demonstrated that muscle-derived stem/progenitor cells (MDSPCs) isolated from adult human skeletal muscle (hMDSPCs) can adopt neuronal and glial phenotypes in vitro and ameliorate a critical-sized sciatic nerve injury and its associated defects in a murine model. Transplanted hMDSPCs surrounded the axonal growth cone, while hMDSPCs infiltrating the regenerating nerve differentiated into myelinating Schwann cells. Engraftment of hMDSPCs into the area of the damaged nerve promoted axonal regeneration, which led to functional recovery as measured by sustained gait improvement. Furthermore, no adverse effects were observed in these animals up to 18 months after transplantation. Following hMDSPC therapy, gastrocnemius muscles from mice exhibited substantially less muscle atrophy, an increase in muscle mass after denervation, and reorganization of motor endplates at the postsynaptic sites compared with those from PBS-treated mice. Evaluation of nerve defects in animals transplanted with vehicle-only or myoblast-like cells did not reveal histological or functional recovery. These data demonstrate the efficacy of hMDSPC-based therapy for peripheral nerve injury and suggest that hMDSPC transplantation has potential to be translated for use in human neuropathies.

Authors

Mitra Lavasani, Seth D. Thompson, Jonathan B. Pollett, Arvydas Usas, Aiping Lu, Donna B. Stolz, Katherine A. Clark, Bin Sun, Bruno Péault, Johnny Huard

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Figure 1

hMDSPCs adopt morphology and express markers of neuronal and glial cells under controlled culture conditions.

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hMDSPCs adopt morphology and express markers of neuronal and glial cells...
Shown are representative images from at least six independent experiments from four hMDSPC populations (A) Bright-field image of hMDSPC-derived neurospheres 2 days after induction. Seven- to 8-day-old hMDSPC-derived neurospheres immunostained for (B) neuronal marker Tuj1 and (C) astrocytic and Schwann cell marker GFAP. (D) Dissociated 7- to 8-day-old neurospheres stained for Tuj1 (red) and S100 (green). Arrowhead shows cells Tuj1+ (red), and arrow indicates coexpression of Tuj1 and S100 (yellow). Terminally differentiated neurospheres at 14 to 27 days contain neurons expressing (E) Tuj1 and (F) MAP2 and cells expressing glial and Schwann cell markers (G) SOX10, (H) S100, (I) p75, (J) peripherin, (K) GFAP+ astrocyte type 1, and (L) GFAP+ astrocyte type 2. Tuj1+ cells show (J) bipolar and (K) tripolar neurons. The nuclear counterstain is DAPI (blue) or human lamin A/C (green). (O) Real-time RT-PCR was performed to measure expression levels of neural progenitor cell markers (PAX6 and NES), neuronal markers (TUBB, NEFH, and MAP2), and glial and Schwann cell markers (S100B, GFAP, and CLDN11) between undifferentiated hMDSPCs, hMDSPC-derived neurospheres, and terminally differentiated hMDSPCs. Error bars indicate the mean ± SD from three independent hMDSPC populations; *P < 0.05, Tukey’s test. Original magnification, ×20 (A–C, E–G, I, J, and L) and ×40 (D, H, K, M, N, and inset in G).