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Stem Cells. 2019 Mar 5. doi: 10.1002/stem.2998. [Epub ahead of print]

Survival/adaptation of Bone Marrow derived Mesenchymal Stem Cells after long term starvation through selective processes.

Author information

1
Regenerative Medicine Institute (REMEDI), School of Medicine, National University of Ireland Galway (NUIG), Galway, Ireland.
2
Neuroscience Area, International School for Advanced Studies (SISSA), Trieste, Italy.
3
Department of Clinical Biochemistry, Saolta University Health Care Group (SUHCG), Galway University Hospitals, Galway, Ireland.

Abstract

After in vivo transplantation Mesenchymal Stem Cells (MSC) face an ischemic microenvironment, characterized by nutrient deprivation and reduced oxygen tension, which reduces their viability and thus their therapeutic potential. Therefore, MSC response to models of in vitro ischemia is of relevance for improving their survival and therapeutic efficacy. The aim of this study is to understand the survival/adaptive response mechanism that MSC use to respond to extreme culture conditions. Specifically, the effect of a long term starvation on human bone marrow derived mesenchymal stem cells cultured in a chemically defined medium (fetal bovine serum-free and human serum-free), either in hypoxic or normoxic conditions. We observed that human Bone Marrow Mesenchymal Stem Cells (hBM-MSC) that were isolated and cultured in SF medium and subjected to a complete starvation for up to 75 days transiently changed their behavior and phenotype. However, at the end of that period, hBM-MSC retained their characteristics as determined by their morphology, DNA damage resistance, proliferation kinetic and differentiation potential. This survival mode involved a quiescent state, confirmed by increased expression of cell cycle regulators p16, p27, p57 and decreased expression of PCNA, Ki-67, mTOR and Nanog. In addition, Jak/STAT (STAT6) anti-apoptotic activity selected which cells conserved stemness and that supported metabolic, bioenergetic and scavenging requirements. We also demonstrated that hBM-MSC exploited an autophagic process which induced lipid β-oxidation as an alternative energy source. Priming MSCs by concomitant starvation and culture in hypoxic conditions to induce their quiescence, would be of benefit to increase MSC survival when transplanted in vivo. SIGNIFICANCE STATEMENT: MSC response to models of in vitro ischemia is of great interest for improving their survival and therapeutic efficacy. Understanding the effect of cell priming in serum-free medium, by concomitant starvation and culture in hypoxic conditions to induce their quiescence, would be of benefit to increase their survival rate when transplanted in vivo, as well as to enable the development of new improved culture protocols before MSC transplantation. MSC primed in this way may not only have the capacity to secrete trophic factors, increasing angiogenesis and reducing inflammation but also survive, fully integrate and differentiate into the regenerating site.

KEYWORDS:

Autophagy; Cell metabolism; Cell survival; Human Bone Marrow Stem cells; Ischemia; Quiescence; STAT6

PMID:
30835892
DOI:
10.1002/stem.2998

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