Fusion of Human Fetal Mesenchymal Stem Cells with “Degenerating” Cerebellar Neurons in Spinocerebellar Ataxia Type 1 Model Mice

Abstract

Mesenchymal stem cells (MSCs) migrate to damaged tissues, where they participate in tissue repair. Human fetal MSCs (hfMSCs), compared with adult MSCs, have higher proliferation rates, a greater differentiation capacity and longer telomeres with reduced senescence. Therefore, transplantation of quality controlled hfMSCs is a promising therapeutic intervention. Previous studies have shown that intravenous or intracortical injections of MSCs result in the emergence of binucleated cerebellar Purkinje cells (PCs) containing an MSC-derived marker protein in mice, thus suggesting a fusion event. However, transdifferentiation of MSCs into PCs or transfer of a marker protein from an MSC to a PC cannot be ruled out. In this study, we unequivocally demonstrated the fusion of hfMSCs with murine PCs through a tetracycline-regulated (Tet-off) system with or without a Cre-dependent genetic inversion switch (flip-excision; FLEx). In the FLEx-Tet system, we performed intra-cerebellar injection of viral vectors expressing tetracycline transactivator (tTA) and Cre recombinase into either non-symptomatic (4-week-old) or clearly symptomatic (6–8-month-old) spinocerebellar ataxia type 1 (SCA1) mice. Then, the mice received an injection of 50,000 genetically engineered hfMSCs that expressed GFP only in the presence of Cre recombinase and tTA. We observed a significant emergence of GFP-expressing PCs and interneurons in symptomatic, but not non-symptomatic, SCA1 mice 2 weeks after the MSC injection. These results, together with the results obtained using age-matched wild-type mice, led us to conclude that hfMSCs have the potential to preferentially fuse with degenerating PCs and interneurons but not with healthy neurons.

Preclinical Assessment of Mesenchymal-Stem-Cell-Based Therapies in Spinocerebellar Ataxia Type 3

“…Surprisingly, the HNA antibody seems to stain cells in the Purkinje layer for all of the timepoints analyzed ( Figure S8C,E–H ). In fact, previous studies have already reported the fusion of hMSCs with the Purkinje cell layer when injected in murine models of SCA1 [ 63 ] and EAE [ 64 ], suggesting migration of hMSCs to mediate neuroprotection or rescue of highly differentiated sites. Nevertheless, and in spite of these observations, according to our behavioral analysis, hMSCs injected into the cerebellum of SCA3/MJD mice do not cause an amelioration of disease symptoms.…”

Therapeutic Strategies for Spinocerebellar Ataxia Type 1

“…Instead of targeting either ATXN1 or other molecules involved in disease pathology, another therapeutic strategy aims to replace the cells that undergo neurodegeneration in SCA1 using stem cell replacement [119]. Several stem cell types can be used for replacement therapies, including pluripotent stem cells (PSCs) and multipotent stem cells, such as neural progenitor cells (NPCs) and mesenchymal stem cells (MSCs) (Table 4, [21,[119][120][121][122][123][124][125]). in the symptomatic mice [124] MSCs are multipotent and reside in several tissues but mainly in the bone marrow and fat, where they support hematopoiesis and produce cells of the mesodermal lineage.…”

Mesenchymal Stromal Cells’ Therapy for Polyglutamine Disorders: Where Do We Stand and Where Should We Go?

“…Cell fusion was also described to occur by some authors. Of note, this mechanism was described in a SCA1 mouse model, where Purkinje cells (PCs) of the host animals fused with MSC (Huda et al, 2016 ). However, this mechanism is rare in the literature and does not appear to account significantly for MSC’s overall outcomes.…”