Mesenchymal Stromal Cell Therapeutic Potential to Restore Neurovascular Integrity in Machado-Joseph Disease

Abstract Background Machado-Joseph disease (MJD), or Spinocerebellar Ataxia type 3 (SCA3), is a neurodegenerative disorder caused by an expansion of the CAG repeat in the MJD1/ATXN3 gene, which encodes for a polyglutamine-expansion in Ataxin-3. Similar to what occurs in other neurodegenerative disorders, the cerebrovascular system, particularly the blood-brain barrier (BBB), is impaired in MJD. BBB is an important cellular barrier that controls homeostasis of the central nervous system, and its disruption compromises neuronal function. To date, there is no disease-modifying therapy for MJD. Our group previously demonstrated that MSC administration can ameliorate the phenotype of MJD transgenic mice. However, the effect of MSC on the neurovascular unit and BBB integrity remains unexplored in the context of MJD. In the present work, we aimed to evaluate the therapeutic potential of MSC in mitigating vascular abnormalities and BBB disruption in MJD. Methods Eight-month-old MJD transgenic mice were treated with two consecutive bone marrow-MSC intravenous injections (1 week apart). Behavioral tests to assess motor coordination were conducted before and after treatment. Vascular structure, function, and BBB disruption were evaluated by immunohistochemistry and western blot. Results MSC administration partially restored vascular impairment in MJD transgenic mice. Treated mice exhibited improved gait and motor performance footprint and beam walking tests) and concurrently attenuated vascular dysfunction. Specifically, MSC-treated mice exhibited a decrease in collagen IV surface area and stabilized cerebellar blood supply. Additionally, MSC treatment diminished BBB permeability to the Evans blue (EB) dye in MJD mice and restored the levels of important adherent and tight junction-associated proteins in the cellular membrane, including vascular endothelial cadherin (VE-cadherin), claudin-5, and occludin, in a sex-specific manner. Conclusions our results highlight significant cerebrovascular dysregulations in MJD, which are sex-dependent and progress with the disease stage. Moreover, our findings suggest that MSC administration partially reverted vascular impairments, providing valuable insights into the mechanisms underlying the therapeutic potential of MSC in MJD. Graphical Abstract MSC treatment partially reverts neurovascular dysregulation in MJD. MJD mice exhibit increased vessel coverage, increased BBB permeability, and altered TJ and AJ expression and subcellular localization. MSC administration modulates vessel coverage, reduces BBB leakage, and partially normalizes TJ/AJ subcellular localization. List of abbreviations: AJ – Adherent junction; BBB – Blood-Brain barrier; MJD- Machado-Joseph disease; MSC – mesenchymal stromal cell; TJ – thigh junction. Created with BioRender.com