Neural and mesenchymal stem cells in animal models of Huntington's disease: past experiences and future challenges

Irina Kerkis, Monica Santoro Haddad, Cristiane Wenceslau Valverde, Sabina Glosman, Irina Kerkis, Monica Santoro Haddad, Cristiane Wenceslau Valverde, Sabina Glosman

Abstract

Huntington's disease (HD) is an inherited disease that causes progressive nerve cell degeneration. It is triggered by a mutation in the HTT gene that strongly influences functional abilities and usually results in movement, cognitive and psychiatric disorders. HD is incurable, although treatments are available to help manage symptoms and to delay the physical, mental and behavioral declines associated with the condition. Stem cells are the essential building blocks of life, and play a crucial role in the genesis and development of all higher organisms. Ablative surgical procedures and fetal tissue cell transplantation, which are still experimental, demonstrate low rates of recovery in HD patients. Due to neuronal cell death caused by accumulation of the mutated huntingtin (mHTT) protein, it is unlikely that such brain damage can be treated solely by drug-based therapies. Stem cell-based therapies are important in order to reconstruct damaged brain areas in HD patients. These therapies have a dual role: stem cell paracrine action, stimulating local cell survival, and brain tissue regeneration through the production of new neurons from the intrinsic and likely from donor stem cells. This review summarizes current knowledge on neural stem/progenitor cell and mesenchymal stem cell transplantation, which has been carried out in several animal models of HD, discussing cell distribution, survival and differentiation after transplantation, as well as functional recovery and anatomic improvements associated with these approaches. We also discuss the usefulness of this information for future preclinical and clinical studies in HD.

Figures

Fig. 1
Fig. 1
Effect of neural stem cells/progenitor cells and mesenchymal stem cell transplantation on Huntington’s disease etiology and progression. Huntington’s disease (HD) is caused by an expansion of (polyQ) repeats within the amino terminus of the huntingtin (HTT) protein, which promotes HTT aggregation and formation of intracellular inclusion bodies. These events lead to microglial activation, which correlates with striatal neuronal dysfunction and neuronal death as well as with reduced expression of striatal D1 and D2 receptors and of neurotrophic factors [136, 137]. In turn, striatal neuronal dysfunction correlates with cortex atrophy, motor deficits and cognitive deficits in HD patients. According to the most updated literature on HD, both neural stem cells (NSCs)/progenitor cells and mesenchymal stem cells (MSCs) improve motor coordination, behavior and memory. NSCs/progenitor cells and MSCs also seem to be able to reduce formation of HTT-ubiquitin aggregates. HD improvements occur as a result of NSC/progenitor cell and MSC transplantation through very similar mechanisms, such as immunomodulation, trophic properties, neurotrophic support and neuronal protection. These mechanisms are well known for MSCs and only marginally recognized for NSCs/progenitor cells [79, 94]. Until now, the great advantage of MSCs, in comparison with NSCs/progenitor cells, are their immunoprivileged properties, few or lack of ethical concerns regarding their origin, significant therapeutic quantities, non-teratogenicity (safety), as well as immunomodulation. Although in vivo differentiation of both cell types has been demonstrated, it is not clear if the number of differentiated cells is sufficient to justify all brain improvements found upon transplantation or whether changes are due to intrinsic cell regeneration. mHTT mutant huntingtin

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