Spinal cord injury (SCI) often leads to persistent functional deficits due to loss of neurons and glia and to limited axonal regeneration after injury. Here we report that transplantation of human dental pulp stem cells into the completely transected adult rat spinal cord resulted in marked recovery of hind limb locomotor functions. Transplantation of human bone marrow stromal cells or skin-derived fibroblasts led to substantially less recovery of locomotor function. The human dental pulp stem cells exhibited three major neuroregenerative activities. First, they inhibited the SCI-induced apoptosis of neurons, astrocytes, and oligodendrocytes, which improved the preservation of neuronal filaments and myelin sheaths. Second, they promoted the regeneration of transected axons by directly inhibiting multiple axon growth inhibitors, including chondroitin sulfate proteoglycan and myelin-associated glycoprotein, via paracrine mechanisms. Last, they replaced lost cells by differentiating into mature oligodendrocytes under the extreme conditions of SCI. Our data demonstrate that tooth-derived stem cells may provide therapeutic benefits for treating SCI through both cell-autonomous and paracrine neuroregenerative activities.
Stem cells from human exfoliated deciduous teeth (SHED) reside within the perivascular niche of the dental pulp. They are thought to originate from the cranial neural crest, and express early markers for both mesenchymal and neuroectodermal stem cells. 1,2 We previously showed that SHED transplantation into the completely transected rat spinal cord results in remarkable functional recovery of hindlimb locomotion.2 However, whether engrafted SHED or the paracrine factors derived from them can offer therapeutic benefits in other neurological disease settings is still largely unknown. In this study, we investigated the therapeutic benefits of SHED on mouse neonatal hypoxia-ischemia (HI). Materials and MethodsAn expanded version of the Methods section is available in the online-only Data Supplement. SHED, human skin fibroblasts, and their serum-free conditioned medium (CM) were prepared as described. 2The SHED's multi-differentiation potential and their expression of both mesenchymal stem cell and neural lineage markers were similar to those reported previously.2 HI brain injury was induced in postnatal day 5 (P5) mice as described. Cells (2×10 5 ) in 2 μL phosphate buffered saline or phosphate buffered saline alone (as a control) were transplanted into the ipsilateral hemisphere at 2.0 mm anterior and 2.0 mm lateral to bregma, and 2.0 mm deep to the dural surface, using a glass needle and a Kopf microstereotaxic injection system, 24 hours after HI ( Figure 1A). These animals were given daily administration of cyclosporin A (Novartis, Nurnberg, Germany, 10 mg/kg, IP) throughout the experimental period, except when they were used for cytokine expression analysis. For the experiments using CM, mice were given a 2-μL injection of CM or Dulbecco's modification of Eagle's medium (as a control) without cyclosporin A treatment. The animals' neurological recovery was examined by a foot-fault test in 4-, 6-, and 8-week-old HI mice.3 Tissue loss was examined by staining with hematoxylin and eosin, and brain injury was evaluated using a neuropathological scoring system, 4,5 by an observer blinded to the identity of the animal group. The level of apoptosis was analyzed by staining with anticaspase-3 (Cell Signaling). Real-time reverse transcription PCR was carried out as described.2 GAPDH cDNA was amplified as an internal control. Primer sequences are shown in the online-only Supplemental Table 1.Data are expressed as means±SEM. Survival data were analyzed by applying the Kaplan-Meier curve, followed by the Mental-Cox Background and Purpose-Perinatal hypoxia-ischemia (HI) has high rates of neurological deficits and mortality. So far, no effective treatment for HI brain injury has been developed. In this study, we investigated the therapeutic effects of stem cells from human exfoliated deciduous teeth (SHED) for the treatment of neonatal HI brain injury. Methods-Unilateral HI was induced in postnatal day 5 (P5) mice. Twenty-four hours later, SHED, human skin fibroblasts, or serum-free conditioned medium derived from these ...
Skeletal muscle atrophy and the inhibition of muscle regeneration are known to occur as a natural consequence of aging, yet the underlying mechanisms that lead to these processes in atrophic myofibers remain largely unclear. Our research has revealed that the maintenance of proper mitochondrial-associated endoplasmic reticulum membranes (MAM) is vital for preventing skeletal muscle atrophy in microgravity environments. We discovered that the deletion of the mitochondrial fusion protein Mitofusin2 (MFN2), which serves as a tether for MAM, in human iPS cells or the reduction of MAM in differentiated myotubes caused by microgravity interfered with myogenic differentiation process and an increased susceptibility to muscle atrophy, as well as the activation of the Notch signaling pathway. The atrophic phenotype of differentiated myotubes in microgravity and the regenerative capacity of Mfn2-deficient muscle stem cells in dystrophic mice were both ameliorated by treatment with the gamma-secretase inhibitor DAPT. Our findings demonstrate how the orchestration of mitochondrial morphology in differentiated myotubes and regenerating muscle stem cells plays a crucial role in regulating Notch signaling through the interaction of MAM.
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