Neurodegenerative diseases, including Parkinson's disease (PD), Alzheimer's disease, or amyotrophic lateral sclerosis (ALS), among many others, are a heterogeneous group of debilitating disorders with multifactorial etiologies and pathogenesis. Their prevalence is on the rise with the increasing global population and average lifespan; and, despite many treatment approaches have been tested, there are currently no effective preventive or clear therapeutic options. Multifactorial nature of such disorders involves different molecular with impaired bioenergetics. Indeed, mitochondrial dysfunction, directly implicated in the cell bioenergetics, is emerging as an important feature in the etiopathogenesis of these age-related neurodegenerative diseases. Previous findings of our group demonstrated suboptimal bioenergetics profile in a fibroblast models derived from in different genetic forms PD patients (1–3).
Adult stem cells are multi-potent undifferentiated cells found in some tissues of the adult organisms. These cells are capable of self-renewal and differentiate into specialized cells and represent a promising tool for replacement cell therapy purposes in a panoply of diseases, including neurodegenerative disorders. Growing body of evidence underpinning the potential of stem cell approaches in neurodegeneration is continuously emerging in the recent literature, such as the finding that dental pulp stem cells stimulate neuronal differentiation of PC12 cells (4).
From adult stem cells, adipose stem cells are also considered a highly encouraging implement for regenerative medicine (5). Adipose tissue is the most abundant and accessible source of adult stem cells. The relatively minimal invasive collection procedure, the adult stem cells ability for differentiation into different cell lineages, as well as their safe autologous transplantation are the factors that allow adipose stem cells as an alternative source for bone marrow cells (6). Adipose tissue is composed of mature adipocytes and heterogenous cell population including stromal vascular fraction (7). The vascular fraction is consisted of various cell types, such as immune cells, fibroblasts, pericytes, endothelial cells, and adipogenic progenitor stromal cells, which attach together by collagen fibers (5). In culture, human adipose-derived stem cells (hASC) express cell surface markers that are similar to those expressed by mesenchymal stem cells, including CD105, SH3, CD90, and CD44; however, they do not express the hematopoietic marker CD45 and the endothelial marker CD31 (8, 9). As adipose tissue contains such a heterogenous population of partially differentiated cells of adipocyte lineage, tissue repair, angiogenesis and neovascularization may be closely linked to the function of hASC in a complex relationship (10). Due to such convoluted interactions and heterogenous features within the adipose tissue, specific biological mechanisms involved in hASC proper functioning and homeostasis, including stem pluripotency/transdifferentiation capacities as well as bioenergetic fingerprint, remains unknown. Interestingly both stem (11) and bioenergetic (12) tools, explored in the present study, have been proposed as promising therapeutic novel targets in the neurologic field.
Epigenesis has been reported to be involved in the cellular differentiation during development, which is controlled by different factors such as growth and environmental factors (13). These factors are involved directly or indirectly in the transcription and expression of genes by genetic reprogramming process (14). For example, adipose derived stem cells could be induced into neural and glial phenotypes by transdifferentiation mechanism (11).
There are convincing findings demonstrating the relevance of nervous regulation of adipose tissue on metabolic and secretory activities, including plasticity (proliferation, differentiation, trans-differentiation, apoptosis) (15, 16). The neuronal feedback cycle between adipose tissues and brain plays a crucial role in energetic homeostasis. The oxidative and lipolytic metabolic nature of neuronal and adipose tissues, respectively, confers a higher level of complexity in their relationship and in the molecular studies carried out in both biologic sources and derived cell models, especially, those related to bioenergetics. Although little is known about bioenergetic profile of hASC, a recent study exploring hASC bioenergetics demonstrated for the first time, that this stem cells can affect metabolic homeostasis by promoting damaged mitochondrial clearance through mitophagy, thereby delaying aging (17).
The rationale of the present study is to assess hASC potential to transdifferentiate into neuronal-like cells (NhASC and neurospheres), together with the assessment of their bioenergetic fingerprint. To this purpose, hASC derived from both healthy controls and clinical diagnosed PD (PD) patients were included in this study.
The present work contributes to knowledge of characterization of a stem cell model and their bioenergetic profile as potential useful novel target for treating the neurodegenerative condition.