Senescence in Human Mesenchymal Stem Cells: Functional Changes and Implications in Stem Cell-Based Therapy.

Valentina Turinetto,Claudia Giachino,Emanuela Vitale

doi:10.3390/ijms17071164

Valentina Turinetto, Claudia Giachino + Show 1 more

Open Access

https://doi.org/10.3390/ijms17071164

Copy DOI

Abstract

Regenerative medicine is extensively interested in developing cell therapies using mesenchymal stem cells (MSCs), with applications to several aging-associated diseases. For successful therapies, a substantial number of cells are needed, requiring extensive ex vivo cell expansion. However, MSC proliferation is limited and it is quite likely that long-term culture evokes continuous changes in MSCs. Therefore, a substantial proportion of cells may undergo senescence. In the present review, we will first present the phenotypic characterization of senescent human MSCs (hMSCs) and their possible consequent functional alterations. The accumulation of oxidative stress and dysregulation of key differentiation regulatory factors determine decreased differentiation potential of senescent hMSCs. Senescent hMSCs also show a marked impairment in their migratory and homing ability. Finally, many factors present in the secretome of senescent hMSCs are able to exacerbate the inflammatory response at a systemic level, decreasing the immune modulation activity of hMSCs and promoting either proliferation or migration of cancer cells. Considering the deleterious effects that these changes could evoke, it would appear of primary importance to monitor the occurrence of senescent phenotype in clinically expanded hMSCs and to evaluate possible ways to prevent in vitro MSC senescence. An updated critical presentation of the possible strategies for in vitro senescence monitoring and prevention constitutes the second part of this review. Understanding the mechanisms that drive toward hMSC growth arrest and evaluating how to counteract these for preserving a functional stem cell pool is of fundamental importance for the development of efficient cell-based therapeutic approaches.

Highlights

The maintenance and repair of adult tissues and organ are guaranteed by the adult stem cell pool
HMSCs are characterized by their capability to adhere to plastic, develop as fibroblast colony-forming-units, and differentiate into osteocytes, chondrocytes, and adipocytes
Be of great significance to monitor the occurrence of a senescent phenotype in Human MSCs (hMSCs) addressed to clinical uses and to evaluate the functional consequences of senescence in hMSCs which could affect their clinical therapeutic potential, taking into account their paracrine effects, immunomodulatory activity, differentiation potential, and cell migration ability [14]

Summary

Introduction

The maintenance and repair of adult tissues and organ are guaranteed by the adult stem cell pool. Most of the beneficial effects mediated by hMSC cell therapy involved the broad repertoire of secreted trophic factors (commonly referred to as the MSC secretome) exhibiting diverse functions such as immunomodulation, anti-inflammatory activity, angiogenesis regulation, and anti-apoptotic activity. Due to their high proliferative potential, multipotency, paracrine effect, and immunomodulatory activity, MSCs are ideal candidates for regenerative medicine and immunotherapy [4,5]. Be of great significance to monitor the occurrence of a senescent phenotype in hMSCs addressed to clinical uses and to evaluate the functional consequences of senescence in hMSCs which could affect their clinical therapeutic potential, taking into account their paracrine effects, immunomodulatory activity, differentiation potential, and cell migration ability [14]

Senescence Activation in hMSCs and Phenotypic Characterization

FFuunncctitoionnaallAAltlteerraattiioonnssiinnSSeenneesscceenntthhMMSSCCss

Tools to Monitor hMSC Senescence in Vitro

Method

Findings

Tools to Prevent in Vitro hMSC Senescence