Mesenchymal stem cells attenuate peripheral neuronal degeneration in spinocerebellar ataxia type 1 knockin mice

Abstract

Spinocerebellar ataxia type 1 (SCA1) is a devastating neurodegenerative disorder in which an abnormally expanded polyglutamine tract is inserted into causative ataxin-1 proteins. We have previously shown that SCA1 knockin (SCA1-KI) mice over 6 months of age exhibit a degeneration of motor neuron axons and their encasing myelin sheaths, as reported in SCA1 patients. We examined whether axon degeneration precedes myelin degeneration or vice versa in SCA1-KI mice and then attempted to mitigate motor neuron degeneration by intrathecally administering mesenchymal stem cells (MSCs). Temporal examination of the diameters of motor neuron axons and their myelin sheaths revealed a decrease in diameter of the axon but not of the myelin sheaths in SCA1-KI mice as early as 1 month of age, which suggests secondary degeneration of the myelin sheaths. We injected MSCs into the intrathecal space of SCA1-KI mice at 1 month of age, which resulted in a significant suppression of degeneration of both motor neuron axons and myelin sheaths, even 6 months after the MSC injection. Thus, MSCs effectively suppressed peripheral nervous system degeneration in SCA1-KI mice. It has not yet been clarified how clinically administered MSCs exhibit significant therapeutic effects in patients with SCA1. The morphological evidence presented in this current mouse study might explain the mechanisms that underlie the therapeutic effects of MSCs that are observed in patients with SCA1. V C 2015 Wiley Periodicals, Inc.

Human dental stem cell derived transgene‐free iPSCs generate functional neurons via embryoid body‐mediated and direct induction methods

“…For MSCs in dental tissues such as human dental pulp stem cells (hDPSCs), one report showed that hDPSCs cannot mature into functional neurons (Aanismaa et al, ), whereas a more recent study was able to demonstrate electrophysiological characteristics of functional neurons derived from hDPSCs (Gervois et al, ). In general, more consistent findings on MSCs are that they tend to play a supporting role in neurogenesis by preventing cell apoptosis, providing neurotropic factors, and differentiating into glial cells instead of becoming neurons (Chen, Wang, Lu, Zhang, & Chopp, ; Hofstetter et al, ; Huang, Snyder, Cheng, & Chan, ; Kopen, Prockop, & Phinney, ; Lee et al, ; Mantovani, Terenghi, & Shawcross, ; Mieda et al, ; Sakai et al, ).…”

Genetics, Mechanisms, and Therapeutic Progress in Polyglutamine Spinocerebellar Ataxias

“…Chang et al [ 277 ] showed that intravenous injection of MSCs in SCA2 mice improved rotarod performance and Purkinje cell survival, while intracranial transplantation failed to achieve these neuroprotective effects [ 277 ]. Intrathecal injection of MSCs and intravenous injection of MSC-conditioned medium ameliorated both cerebellar pathology and behavior phenotypes in different mouse models of SCA1 and SCA3 [ 275 , 276 , 278 , 291 ]. The first phase 1/2 clinical trials to evaluate the safety, tolerability, and efficacy of intrathecal injection or intravenous administration of MSCs from healthy donors in polyQ SCA patients have been performed [ 292 – 295 ].…”

Morphological and Functional Attenuation of Degeneration of Peripheral Neurons by Mesenchymal Stem Cell‐Conditioned Medium in Spinocerebellar Ataxia Type 1‐Knock‐in Mice

“…Both axons and myelin degenerate in old SCA1-KI mice [23]. We recently showed that intrathecal injection of MSCs relieves the degeneration of axons and myelin in SCA1-Tg mice [16]. In the current study, we reproduced these morphological improvements using MSC-CM rather than MSCs themselves.…”