Sublethal heat shock induces premature senescence rather than apoptosis in human mesenchymal stem cells

Abstract

Stem cells in adult organism are responsible for cell turnover and tissue regeneration. The study of stem cell stress response contributes to our knowledge on the mechanisms of damaged tissue repair. Previously, we demonstrated that sublethal heat shock (HS) induced apoptosis in human embryonic stem cells. This study aimed to investigate HS response of human adult stem cells. Human mesenchymal stem cells (MSCs) cultivated in vitro were challenged with sublethal HS. It was found that sublethal HS did not affect the cell viability assessed by annexin V/propidium staining. However, MSCs subjected to severe HS exhibited features of stress-induced premature senescence (SIPS): irreversible cell cycle arrest, altered morphology, increased expression of senescence-associated β-galactosidase (SA-β-gal) activity, and induction of cyclin-dependent kinase inhibitor p21 protein. High level of Hsp70 accumulation induced by sublethal HS did not return to the basal level, at least, after 72 h of the cell recovery when most cells exhibited SIPS hallmarks. MSCs survived sublethal HS, and resumed proliferation sustained the properties of parental MSCs: diploid karyotype, replicative senescence, expression of the cell surface markers, and capacity for multilineage differentiation. Our results showed for the first time that in human MSCs, sublethal HS induced premature senescence rather than apoptosis or necrosis. MSC progeny that survived sublethal HS manifested stem cell properties of the parental cells: limited replicative life span and multilineage capacity.

Persistent DNA damage‐induced premature senescence alters the functional features of human bone marrow mesenchymal stem cells

“…This resistance to cell death relies on different mechanisms depending on the different DNA-damaging agents/doses used, including an elevated apoptosis threshold 16, an efficient antioxidant ROS-scavenging capacity 13 and a prompt activation of the double strand break repair pathways 13,17. Our results are in accordance with the more recent literature that described SIPS as a further response of hMSCs to ionizing radiation 21,40, oxidative stress 18,41, heat shock 19.…”

“…Notably, hMSCs showed to be highly resistant to apoptosis induced by different genotoxic insults [11][12][13][14][15][16][17], even though the precise resistance mechanisms are not completely understood. Recently it has been reported that another possible response of hMSCs to injury is stress-induced premature senescence (SIPS) [18][19][20][21][22][23][24]. Even if SIPS represents an important tumour suppressive mechanism that irreversibly prevents damaged cells from undergoing neoplastic transformation, it is clearly a double-edged sword [25].…”

Optimization of lentiviral transduction parameters and its application for CRISPR-based secretome modification of human endometrial mesenchymal stem cells

“…According to our previous data together with the results described in a latter review, MSCs senescence is accompanied by reduced proliferation rate, decreased differentiation potential as well as impaired migratory ability, the outcomes that we revealed after hMESCs infection supplied by Pb [35,[43][44][45]. Therefore, we speculated that the negative effects of transduction with Pb might be mediated by senescence initiation in a part of hMESCs population.…”

“…Summarizing the obtained data, we can make several important conclusions: (1) Transduction with Pb induces senescence in a part of hMESCs population According to the modern data, reduced proliferation and migration rates as well as the decreased differentiation capability of MSCs can testify in favor of senescence progression in the population [43]. Previously, we have convincingly shown that senescence is more preferable reaction of hMESCs in response to damage or stress than apoptosis [44,45]. Based on the data described above, further we analyzed whether senescence induction can be the underlying cause of the observed negative effects of LV infection with Pb.…”

Cryopreserved Mesenchymal Stromal Cells Are Susceptible to T-Cell Mediated Apoptosis Which Is Partly Rescued by IFNγ Licensing

“…Altogether, identically thawed MSCs retain their immune suppressive effect on T‐cell proliferation if they are separated by a physical barrier suggestive that the heat shock response and cytoskeletal disruption in themselves do not abort their suppressor function, but rather that frozen‐thawed MSCs and granzyme+ T‐cells make poor bedfellows. Thus, we speculate that freeze‐thawing induced alterations in the plasma membrane, intracellular pH, and mitochondrial depolarization likely potentiate MSC's susceptibility to T cell mediated killing and may also promote sensitivity to complement‐mediated lysis .…”