Abstract
Adipose-derived mesenchymal stem cells (ASCs) are promising therapeutic tools in regenerative medicine because they possess self-renewal, differentiation and immunomodulatory capacities. After isolation, ASCs are passaged multiple times in vitro passages to obtain a sufficient amount of cells for clinical applications. During this time-consuming procedure, ASCs become senescent and less proliferative, compromising their clinical efficacy. Here, we sought to investigate how in vitro passages impact ASC proliferation/senescence and expression of immune regulatory proteins. MicroRNAs are pivotal regulators of ASC physiology. Particularly, miR-200c is known to maintain pluripotency and targets the immune checkpoint Programmed death-ligand 1 (PD-L1). We therefore investigated its involvement in these critical characteristics of ASCs during in vitro passages. We found that when transiently expressed, miR-200c-3p promotes proliferation, maintains stemness, and contrasts senescence in late passaged ASCs. Additionally, this miRNA modulates PD-L1 and Indoleamine 2,3-Dioxygenase (IDO1) expression, thus most likely interfering with the immunoregulatory capacity of ASCs. Based on our results, we suggest that expression of miR-200c-3p may prime ASC towards a self-renewing phenotype by improving their in vitro expansion. Contrarily, its inhibition is associated with senescence, reduced proliferation and induction of immune regulators. Our data underline the potential use of miR-200c-3p as a switch for ASCs reprogramming and their clinical application.
Highlights
Adipose-derived mesenchymal stem cells (ASCs) represent a population of self-renewing multipotent adult cells
We assessed the expression of stemness markers Nanog, Oct4 and Sox2 in relationship with miR200c-3p expression
A concomitant increase of Nanog, Oct4 and Sox2 at P6 and P9 was followed by a return to basal levels at P15 (Fig 1B)
Summary
Adipose-derived mesenchymal stem cells (ASCs) represent a population of self-renewing multipotent adult cells. They are isolated from the vascular stroma of adipose tissue. The main biological properties of ASCs useful in cell-based therapy are: 1) the ability to proliferate and to maintain their stemness. These are important characteristics for the maintenance of a relatively stable clone of self-renewing cells within the target tissue, 2) the expression of immunomodulatory proteins on the surface of ASCs or secreted enzymes, in the so-called secretome, which enable them to escape immune recognition. ASCs can be used in the clinical treatment of inflammatory and autoimmune pathologies, such as multiple sclerosis, inflammatory bowel disease, graft-versus-host disease (GvHD), rheumatoid arthritis (RA) and other diseases [1,2,3,4,5]
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