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 January 3, 2012
Citation Information: J Clin Invest. 2012;122(1):80-90. doi:10.1172/JCI59251.
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Categories: Research Article Stem cells

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

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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SHEDs suppress the apoptosis of neural cell lineages and secondary injur...

Figure 8

SHEDs suppress the apoptosis of neural cell lineages and secondary injury after SCI.

Representative images (A–L) and quantifications (M and N) of apoptotic cell death 24 hours after SCI. Transverse sections 1 mm caudal to the epicenter of PBS-injected (A, B, E, F, I, and J) and SHED-transplanted SCs (C, D, G, H, K, and L) were stained with TUNEL and then subjected to immunohistochemical analysis with an anti-GFAP mAb (A–D), anti-NeuN mAb (E–H), or anti-MBP mAb (I–L). The engrafted SHEDs decreased the apoptotic cell death of all 3 neural cell lineages. (M) Quantification of the total TUNEL-positive cell number within 3 mm rostral and caudal to the epicenter shows the average of 3 experiments performed in parallel. (N) The percentage of TUNEL-positive relative to total DAPI-positive cell number in the same area as in M. Error bars represent SD. *P < 0.01 compared with SCI models injected with PBS. Scale bar: 20 μm (L).