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Human dental pulp-derived stem cells promote locomotor recovery after complete transection of the rat spinal cord by multiple neuro-regenerative mechanisms
Kiyoshi Sakai, … , Naoki Ishiguro, Minoru Ueda
Kiyoshi Sakai, … , Naoki Ishiguro, Minoru Ueda
Published December 1, 2011
Citation Information: J Clin Invest. 2012;122(1):80-90. https://doi.org/10.1172/JCI59251.
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Research Article

Human dental pulp-derived stem cells promote locomotor recovery after complete transection of the rat spinal cord by multiple neuro-regenerative mechanisms

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Abstract

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.

Authors

Kiyoshi Sakai, Akihito Yamamoto, Kohki Matsubara, Shoko Nakamura, Mami Naruse, Mari Yamagata, Kazuma Sakamoto, Ryoji Tauchi, Norimitsu Wakao, Shiro Imagama, Hideharu Hibi, Kenji Kadomatsu, Naoki Ishiguro, Minoru Ueda

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Figure 1

Characterization of the SHEDs and DPSCs used for transplantation.

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Characterization of the SHEDs and DPSCs used for transplantation.
(A) Fl...
(A) Flow cytometry analysis of the neural cell lineage markers expressed in SHEDs. Note that most of the SHEDs and DPSCs coexpressed neural stem and multiple progenitor markers, but not mature oligodendrocytes (APC and MBP). (B) Confocal images showing SHEDs coexpressed nestin, GFAP, and DCX. SHEDs also expressed markers for oligodendrocyte progenitor cells (A2B5 and CNPase), but not for mature oligodendrocytes (APC and MBP). Scale bar: 10 μm. (C) Real-time RT-PCR analysis of the expression of neurotrophic factors. Results are expressed as fold increase compared with the level expressed in skin fibroblasts. Data represent the average measurements for each cell type from 3 independent donors. This set of experiments was repeated twice and yielded similar results. Data represent the mean ± SEM. *P < 0.01 compared with BMSCs and fibroblasts (Fbs).

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