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

Abstract

Polyglutamine (polyQ) diseases are a group of inherited neurodegenerative disorders caused by the expansion of the cytosine-adenine-guanine (CAG) repeat. This mutation encodes extended glutamine (Q) tract in the disease protein, resulting in the alteration of its conformation/physiological role and in the formation of toxic fragments/aggregates of the protein. This group of heterogeneous disorders shares common molecular mechanisms, which opens the possibility to develop a pan therapeutic approach. Vast efforts have been made to develop strategies to alleviate disease symptoms. Nonetheless, there is still no therapy that can cure or effectively delay disease progression of any of these disorders. Mesenchymal stromal cells (MSC) are promising tools for the treatment of polyQ disorders, promoting protection, tissue regeneration, and/or modulation of the immune system in animal models. Accordingly, data collected from clinical trials have so far demonstrated that transplantation of MSC is safe and delays the progression of some polyQ disorders for some time. However, to achieve sustained phenotypic amelioration in clinics, several treatments may be necessary. Therefore, efforts to develop new strategies to improve MSC’s therapeutic outcomes have been emerging. In this review article, we discuss the current treatments and strategies used to reduce polyQ symptoms and major pre-clinical and clinical achievements obtained with MSC transplantation as well as remaining flaws that need to be overcome. The requirement to cross the blood-brain-barrier (BBB), together with a short rate of cell engraftment in the lesioned area and low survival of MSC in a pathophysiological context upon transplantation may contribute to the transient therapeutic effects. We also review methods like pre-conditioning or genetic engineering of MSC that can be used to increase MSC survival in vivo , cellular-free approaches—i.e., MSC-conditioned medium (CM) or MSC-derived extracellular vesicles (EVs) as a way of possibly replacing the use of MSC and methods required to standardize the potential of MSC/MSC-derived products. These are fundamental questions that need to be addressed to obtain maximum MSC performance in polyQ diseases and therefore increase clinical benefits.

Mesenchymal stem cells for lysosomal storage and polyglutamine disorders: Possible shared mechanisms

“…Different medium composition and devices for cell growth (like bioreactors allowing for 3D cultures) as well as preconditioning methods, such as hypoxia, exposure to inflammatory factors or other chemicals, cell modifications (e.g. to overexpress certain molecules like growth factors or exo‐fucosylation – cell surface glycan modification of CD44) or even the use of MSC in combination with other therapies have been explored to increase cell viability, targeting and/or their therapeutic properties 31‐36 …”

“…Mesenchymal stem cells' therapeutic potential has been investigated for the treatment of several neurodegenerative diseases, such as Alzheimer's disease, Amyotrophic Lateral Sclerosis, Multiple sclerosis, Parkinson's disease, polyglutamine (PolyQ) Spinocerebellar ataxias and Leukodystrophies, obtaining encouraging results 6,18,19,33,36‐49 . At the pre‐clinical level, MSC have been found to promote tissue regeneration, repair and turnover, by increasing cell survival and neurogenesis, inhibiting apoptosis, favouring abnormal aggregate clearance and modulating the immune system, through their paracrine activity 5,8,47,50‐58 …”

“…In the last few years, MSC have also been recognized as a promising therapy for SCAs (reviewed in 36 ). Chang and collaborators have shown that intravenous (iv) delivery of MSC can promote recovery in mice motor function as well as delay disease onset in a transgenic mouse model of SCA‐2 by rescuing cerebellar Purkinje cells 95 .…”

“…Mesenchymal stem cells' therapeutic potential has been investigated for the treatment of several neurodegenerative diseases, such as Alzheimer's disease, Amyotrophic Lateral Sclerosis, Multiple sclerosis, Parkinson's disease, polyglutamine (PolyQ) Spinocerebellar ataxias and Leukodystrophies, obtaining encouraging results. 6,18,19,33,[36][37][38][39][40][41][42][43][44][45][46][47][48][49] At the pre-clinical level, MSC have been found to promote tissue regeneration, repair and turnover, by increasing cell survival and neurogenesis, inhibiting apoptosis, favouring abnormal aggregate clearance and modulating the immune system, through their paracrine activity. 5,8,47,[50][51][52][53][54][55][56][57][58] Indeed, MSC can "sense" the environment created by the signals emitted by injured tissues and home to target areas where they secrete an array of molecules, including cytokines/chemokines and neurotrophic factors.…”

“…Mesenchymal stem cells' immunomodulatory effect has likewise been proven for some PolyQs. 36 A recent study showed that MSC-CM lead to a significant decrease in microglia activation, ameliorating Huntington's disease symptoms in an animal model. 147 Another report showed that the combined administration of MSC and lercanidipine, an anti-hypertensive drug, decreased inflammation and astroglia activation, concomitantly to decreased apoptosis, neuronal loss and phenotypic ameliorations in 3-Nitropropionic acid-induced rat model of Huntington's disease, via modulation of the calcium/calcineurin/ NFATc4 and Wnt/β-catenin signalling pathways.…”