Gene Therapy Based on Mesenchymal Stem Cells Derived from Adipose Tissue for the Treatment of Obesity and Its Metabolic Complications

Abstract

Obesity is a highly prevalent condition often associated with dysfunctional adipose tissue. Stem cell-based therapies have become a promising tool for therapeutic intervention in the context of regenerative medicine. Among all stem cells, adipose-derived mesenchymal stem cells (ADMSCs) are the most easily obtained, have immunomodulatory properties, show great ex vivo expansion capacity and differentiation to other cell types, and release a wide variety of angiogenic factors and bioactive molecules, such as growth factors and adipokines. However, despite the positive results obtained in some pre-clinical studies, the actual clinical efficacy of ADMSCs still remains controversial. Transplanted ADMSCs present a meager rate of survival and proliferation, possibly because of the damaged microenvironment of the affected tissues. Therefore, there is a need for novel approaches to generate more functional ADMSCs with enhanced therapeutic potential. In this context, genetic manipulation has emerged as a promising strategy. In the current review, we aim to summarize several adipose-focused treatments of obesity, including cell therapy and gene therapy. Particular emphasis will be given to the continuum from obesity to metabolic syndrome, diabetes, and underlying non-alcoholic fatty liver disease (NAFLD). Furthermore, we will provide insights into the potential shared adipocentric mechanisms involved in these pathophysiological processes and their remediation using ADMSCs.

Unraveling Adipose Tissue Dysfunction: Molecular Mechanisms, Novel Biomarkers, and Therapeutic Targets for Liver Fat Deposition

“…The results obtained in animal models have confirmed the effects of ADMSC therapy on weight loss, changes in AT composition, and improvement of related comorbidities such as diabetes or NAFLD [ 148 , 161 ].…”

“…In this context, the emergence of genetic engineering techniques and a deeper understanding of the molecular basis of obesity have led to novel precision medicine approaches targeting AT [ 147 ]. These innovative approaches include ADMSC-based therapy and gene therapy for obesity [ 148 ].…”

Designer Fat Cells: Adipogenic Differentiation of CRISPR-Cas9 Genome-Engineered Induced Pluripotent Stem Cells

“…Previous groups have successfully generated brown-like ADMSCs using genome engineering techniques and the beneficial effects of transplantation of these cells into obese mice, including improved glucose tolerance, insulin sensitivity, and increased energy expenditure (Wang et al ., 2020). This efficient approach of generating diverse types of adipose tissue from iPSCs is viable, and it will allow future applications to integrate genome editing with these tissues, creating new possibilities for cell-based therapeutics, as previously explored with adipose-derived stem cells (Lopez-Yus et al ., 2023). By simplifying the downstream differentiation of these three phenotypes of adipocytes, we can then use genome engineering to knock out genes of interest or rewire the different adipocyte depots for drug delivery applications.…”

Efficacy of adipose‐derived mesenchymal stem cell therapy in the treatment of chronic micro‐ and macrovascular complications of diabetes

“…149 In addition, several genetic engineering methods, including viral and non-viral transfection and CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-Cas9 gene editing technology, modify the gene expression profile of MSCs and improve post-transplantation outcomes. 150 Another approach as an alternative to cell therapy is extracellular vesicles (EVs) as important mediators of cell communication and supporting tissue renewal and regeneration. Finally, new technologies are currently being used to improve EVs, such as novel EV production and isolation methods using advanced bioreactors, bioengineering of EV contents, and the use of three-dimensional cultures such as organoids.…”