A novel role of vitronectin in promoting survival of mesenchymal stem cells under serum deprivation stress

Goyal, Umesh; Ta, Malancha

doi:10.1186/s13287-020-01682-y

Cited by 19 publications

(20 citation statements)

References 40 publications

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“…In support, a previous report had shown that growth arrested quiescent human endometrial mesenchymal stem cells were more resistant to heat stress compared to proliferating cells (23). Additionally, earlier report from our lab had also demonstrated the pro-survival effect of VTN in serum deprived WJ-MSCs via mediating G0/G1 cell cycle arrest (16).…”

Section: Discussionsupporting

confidence: 81%

Vitronectin mediates survival of human WJ-MSCs under inflammatory temperature stress via cell cycle arrest

Goyal

2022

Preprint

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Due to their anti-inflammatory and immunomodulatory capabilities, mesenchymal stem cells (MSCs) are being widely used in cell-based therapies for the treatment of a wide spectrum of inflammatory disorders. Despite their promises, substantial cell loss post transplantation leads to compromised therapeutic benefits in clinical trials, which remains a challenge to overcome. Inflammatory microenvironment comprises the presence of pro-inflammatory cytokines, elevated temperature, etc., which could hamper MSC viability following transplantation. Thus, identifying the underlying molecular factors controlling survival mechanism under such stress conditions, thereby, improving MSC survival becomes important for optimising MSC-based therapy. Also, since MSCs from different origins have significantly varied biology, choosing the appropriate MSC source could be crucial in determining the fate of transplanted MSCs in stressful milieu. As extracellular matrix (ECM) components can mediate cell survival signals, in the present study, we have evaluated the role of ECM matricellular protein, vitronectin (VTN), in the survival of human Wharton's Jelly MSCs (WJ-MSCs) under the condition of inflammatory temperature stress. On exposure to 40°C, WJ-MSCs underwent cell cycle arrest with no significant change in viability status, along with an induction in VTN expression both at mRNA and protein levels. Interestingly, inhibition of pro-survival signalling pathways, ERK or PI3K, at 40°C led to further upregulation in VTN expression without any significant impact on viability or cell cycle arrest status. However, on knocking down VTN in WJ-MSCs at 40°C, decrease in viability status along with reversal of cell cycle arrest were noted. Moreover, inhibition of pro-survival pathways ERK or PI3K, in VTN knocked down WJ-MSCs at 40°C, led to a dramatic reduction in the viable population accompanied with reversal in cell cycle arrest. Altogether, our findings highlighted the protective role of VTN in mediating survival of WJ-MSCs under inflammatory temperature stress via adopting cell cycle arrest mechanism.

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Section: Discussionsupporting

confidence: 81%

Vitronectin mediates survival of human WJ-MSCs under inflammatory temperature stress via cell cycle arrest

Goyal

2022

Preprint

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“…As reported previously [16], exposure to serum starved condition resulted in flattened morphology with significant increase in cell spread area (data not shown) and cellular adhesion in WJ-MSCs (Fig. 1A, B).…”

Section: Serum Starvation Impairs the Migration Ability Of The Wj-mscssupporting

confidence: 89%

“…Next, we investigated the expression and regulation of VTN under serum starved condition in co-relation with the phenotypic changes observed. In our previous studies [17,18], we had observed that expression of VTN, an ECM component known to be responsible for cell adhesion, was up-regulated under both serum starvation and febrile temperature stress conditions and this was accompanied by increase in cell spread area and cell adhesion. In the present study under serum starved condition, VTN expression again exhibited a strong upregulation both at mRNA and protein levels, though not significant (Fig.…”

Section: Resultsmentioning

confidence: 99%

Vitronectin acts as a key regulator of adhesion and migration in human umbilical cord-derived MSCs under different stress conditions

Sen

2021

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Mesenchymal stem cell (MSC)-based cellular therapy gets compromised as adverse microenvironmental conditions like nutrient deprivation, ischemia, hypoxia affect migration and engraftment, in addition to viability, of MSCs at the target site post transplantation. To improve the treatment efficacy, it is critical to identify factors involved in regulating migration and adhesion of MSCs under such microenvironmental stress conditions. In our study, we observed that Wharton’s jelly-MSCs (WJ-MSCs) exhibited increase in cell spread area and adhesion with reduction in cellular migration under serum starvation. The changes in adhesion and migration characteristics were accompanied by extensive stress fibre formation and altered ECM gene expression with notable induction in vitronectin (VTN) expression and reduction in MMP-1 expression. Molecular and phenotypic correlative studies advocated the possible role of VTN and not MMP-1, in regulating adhesion and migration of WJ-MSCs. NF-κβ was found to be the positive regulator of VTN expression while ERK pathway regulated it negatively. Further investigation with inhibition of these signalling pathways or VTN knockdown studies under serum starvation established the correlation between increase in VTN expression and increased cellular adhesion with corresponding reduction in migration. VTN knockdown under serum starvation also led to reduction in actin stress fibre along with reversal in expression of several ECM genes. Additionally, VTN induction being absent in hypoxia-treated WJ-MSCs, the hypoxic cells showed no significant change in the adhesion and migration properties. However, when VTN expression was induced under hypoxia by ERK pathway inhibition, similar increase in cell spread area and adhesion was observed. Our study thus highlights VTN as a factor which is induced under serum starvation stress and possibly affects the adhesion and migration properties of WJ-MSCs.

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“…The loosened-up appearance can explain the appearance of larger size under high and extreme stress. Such phenomenon is also observed in a recent study where cells under serum deprivation exhibit increased cell area [54]. Though no negative impact of stress conditions on spheroid growth is observed, an interesting observation emerges from both individual and combined conditions.…”

Section: Discussionsupporting

confidence: 75%

Macro- and micro-nutrient–based multiplex stress conditions modulate in vitro tumorigenesis and aggressive behavior of breast cancer spheroids

et al. 2021

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PurposeThe aggressive nature of a tumor is presumably its inherent one, but different environmental cues can manipulate it in many ways. In this context, the influence of metabolic stresses on tumor behavior needs to be analyzed to understand their far-reaching implications on tumor aggression and dormancy. This work investigates different facets of the tumor, such as tumorigenic capacity, tumor phenotype, and migration, under multiple metabolic stress conditions. Methods Non-invasive and invasive multicellular spheroids (MTS) were created and subjected to multiple stress conditions, namely glucose, amino acid, and oxygen deprivation. Altered behavior of the MTS has been evaluated in the context of in vitro tumorigenesis, spheroid formation capacity, phenotype, mRNA profile, migration, and recruitment of mesenchymal stem cells. ResultsThe metabolic stress conditions were observed to negatively impact the in vitro tumorigenesis and spheroid formation process of invasive and non-invasive breast cancer cells. While the stress seemingly influences the growth and phenotype of spheroids, it does not alter the organization of sub-cellular entities significantly. Metabolic stress conditions impact the transcriptomic landscape of hypoxic, angiogenic, ECM deformation, glycolysis shift, and protein starvation-related gene clusters. MTSs do not adhere or migrate under stress, but they exhibit different modalities of migration when rescued. Invasive spheroids, after the rescue, exhibit increased aggressiveness. Furthermore, stressed spheroid was observed to control the migration and recruitment of mesenchymal stem cells. Conclusion Multiplex metabolic stresses could control the tumorigenesis while influencing the physiology of invasive and non-invasive breast cancer spheroids along with their migration pattern and tumor-stromal crosstalk.

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A novel role of vitronectin in promoting survival of mesenchymal stem cells under serum deprivation stress

Cited by 19 publications

References 40 publications

Vitronectin mediates survival of human WJ-MSCs under inflammatory temperature stress via cell cycle arrest

Vitronectin mediates survival of human WJ-MSCs under inflammatory temperature stress via cell cycle arrest

Vitronectin acts as a key regulator of adhesion and migration in human umbilical cord-derived MSCs under different stress conditions

Macro- and micro-nutrient–based multiplex stress conditions modulate in vitro tumorigenesis and aggressive behavior of breast cancer spheroids

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