Differentiation of Human Tonsil-Derived Mesenchymal Stem Cells into Schwann-Like Cells Improves Neuromuscular Function in a Mouse Model of Charcot-Marie-Tooth Disease Type 1A

Abstract

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited motor and sensory neuropathy, and is caused by duplication of PMP22, alterations of which are a characteristic feature of demyelination. The clinical phenotype of CMT1A is determined by the degree of axonal loss, and patients suffer from progressive muscle weakness and impaired sensation. Therefore, we investigated the potential of Schwann-like cells differentiated from human tonsil-derived stem cells (T-MSCs) for use in neuromuscular regeneration in trembler-J (Tr-J) mice, a model of CMT1A. After differentiation, we confirmed the increased expression of Schwann cell (SC) markers, including glial fibrillary acidic protein (GFAP), nerve growth factor receptor (NGFR), S100 calcium-binding protein B (S100B), glial cell-derived neurotrophic factor (GDNF), and brain-derived neurotrophic factor (BDNF), which suggests the differentiation of T-MSCs into SCs (T-MSC-SCs). To test their functional efficiency, the T-MSC-SCs were transplanted into the caudal thigh muscle of Tr-J mice. Recipients’ improved locomotive activity on a rotarod test, and their sciatic function index, which suggests that transplanted T-MSC-SCs ameliorated demyelination and atrophy of nerve and muscle in Tr-J mice. Histological and molecular analyses showed the possibility of in situ remyelination by T-MSC-SCs transplantation. These findings demonstrate that the transplantation of heterologous T-MSC-SCs induced neuromuscular regeneration in mice and suggest they could be useful for the therapeutic treatment of patients with CMT1A disease.

A transcriptomic analysis of serial-cultured, tonsil-derived mesenchymal stem cells reveals decreased integrin α3 protein as a potential biomarker of senescent cells

“…The growth medium was changed every 3 days. In vitro-cultured TMSCs were divided into two groups as follows: control TMSCs (passages 5-8) and culture-aged TMSCs (passages [20][21][22][23][24][25]. Morphological changes in the TMSCs were monitored daily by examination under an inverted microscope (Olympus, Tokyo, Japan).…”

“…3a-d). [20][21][22][23][24][25]. c Transcriptomic microarray analysis of differential gene expression between control and culture-aged TMSCS .d ECM-receptor interaction-related genes were identified by KEGG pathway analysis.…”

“…Human tonsil-derived MSCs (TMSCs) are obtained from discarded children's tonsillar tissues after tonsillectomy. TMSCs have been considered as a potential therapeutic tool in the application of tissue engineering and regenerative medicine [14][15][16], because of their high regenerative capacity and multipotency to differentiate into various cell types, such as the bone [17], cartilage [17], adipose [18], muscle [19,20], tendon [21], stroma, and neuronal cells [22,23]. Unfortunately, a long-term culture of TMSCs could lead to replicative senescence, decreasing the stemness and multi-differentiation potential of TMSCs.…”

Application of Tonsil-Derived Mesenchymal Stem Cells in Tissue Regeneration: Concise Review

“…Myelination by the TMSCs differentiated into Schwann cell‐like cells was observed around the axons of cocultured mouse dorsal root ganglion. Moreover, the implantation of the differentiated TMSCs resulted in regeneration of nerves and recovery of neuromuscular function in mice models with sciatic nerve injuries and improvement of neuromuscular function in a mouse model of Charcot–Marie–Tooth disease type 1 .…”

“…Similar to BM‐MSCs, TMSCs have a potential to differentiate into either neuron‐like or glial cells . In a 3D hybrid thermogel that fabricates growth factor‐releasing microspheres, TMSCs expressed phenotypes similar to immature neurons, exhibiting multipolar elongation with weak expression of neuronal markers such as neuronal growth factor, nuclear receptor‐related protein, and neuron‐specific enolase .…”