Hypoxia preconditioning elicit differential response in tissue-specific MSCs via immunomodulation and exosomal secretion

Gupta, Suchi; Rawat, Sonali; Krishnakumar, V.; Rao, Ercole; Mohanty, Sujata

doi:10.1007/s00441-022-03615-y

Cited by 18 publications

(21 citation statements)

References 44 publications

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“…In addition, the combination of serum-free condition and hypoxia preconditioning has a limited effect on the secretome composition. Our results further indicated that serum-free media and hypoxia preconditioning for 48h did not affect hASC’s spindle-shaped cell morphology and viability, consistent with previous studies [ 40 , 47 , 48 ]. The predicted PPI and the protein array profiling of NCM and HCM secretomes showed that the synergism employed here caused no substantial alteration of the paracrine factor landscape, with only minimal significant differences between these two types of secretomes.…”

Section: Discussionsupporting

confidence: 92%

Secretome from human adipose-derived mesenchymal stem cells promotes blood vessel formation and pericyte coverage in experimental skin repair

et al. 2022

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Human adipose tissue-derived stem cells (hASC) secretome display various therapeutically relevant effects in regenerative medicine, such as induction of angiogenesis and tissue repair. The benefits of hASC secretome are primarily orchestrated by trophic factors that mediate autocrine and paracrine effects in host cells. However, the composition and the innate characteristics of hASC secretome can be highly variable depending on the culture conditions. Here, we evaluated the combined effect of serum-free media and hypoxia preconditioning on the hASCs secretome composition and biological effects on angiogenesis and wound healing. The hASCs were cultured in serum-free media under normoxic (NCM) or hypoxic (HCM) preconditioning. The proteomic profile showed that pro- and anti-antiangiogenic factors were detected in NCM and HCM secretomes. In vitro studies demonstrated that hASCs secretomes enhanced endothelial proliferation, survival, migration, in vitro tube formation, and in vivo Matrigel plug angiogenesis. In a full-thickness skin-wound mouse model, injection of either NCM or HCM significantly accelerated the wound healing. Finally, hASC secretomes were potent in increasing endothelial density and vascular coverage of resident pericytes expressing NG2 and nestin to the lesion site, potentially contributing to blood vessel maturation. Overall, our data suggest that serum-free media or hypoxic preconditioning enhances the vascular regenerative effects of hASC secretome in a preclinical wound healing model.

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Section: Discussionsupporting

confidence: 92%

Secretome from human adipose-derived mesenchymal stem cells promotes blood vessel formation and pericyte coverage in experimental skin repair

et al. 2022

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“…Interestingly, MSCs HYP had higher expression of HIF-1α from 6 to 12 hours followed by a decline in their expression from 24 to 48 hours at the gene and protein level consistent with our previous findings (33). We observed a significant alteration in the morphology of hypoxia-preconditioned apoptotic MSCs similar to the previous observations (10,11,48,49).…”

Section: Discussionsupporting

confidence: 91%

“…HIF-1α gene which undergoes ubiquitination in normoxic conditions but becomes stabilized following exposure to hypoxia. Consequently, the expression levels of this gene serve as an indicator of the cellular response to hypoxic conditions (33). Interestingly, both MSCs (BM, WJ) had higher expression of HIF-1α from 6 hours (5.085±0.0495, 8.349±0.454-fold change) to 12 hours (9.65±0.161, 14.420±0.665 fold change) followed by a decline in their expression from 24 hours (6.382±0.059, 10.324±0.119 fold change) to 48 hours (4.288±0.656, 5.470±0.334 fold change) at the gene and protein level (Figure 1F, G).…”

Section: Resultsmentioning

confidence: 99%

Synergistic Hypoxia and Apoptosis Conditioning Unleashes Superior Mesenchymal Stem Cells Efficacy in Acute Graft-versus-Host-Disease

Mendiratta,

Ganguly

et al. 2024

Preprint

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Mesenchymal stem cells (MSCs) have emerged as promising candidates for immune modulation in various diseases that are associated with dysregulated immune responses like Graft-versus-Host-Disease (GVHD). MSCs are pleiotropic and the fate of MSCs following administration is a major determinant of their therapeutic efficacy. In this context, we here demonstrate that hypoxia preconditioned apoptotic MSCs (bone marrow (BM), Wharton Jelly (WJ)) bear more immune programming ability in a cellular model of acute Graft-versus-Host-Disease (aGVHD). To this purpose, we programmed MSCs by exposing them to hypoxia and inducing apoptosis both sequentially as well as simultaneously. Our findings demonstrated that WJ MSCs that were conditioned with indicated approaches simultaneously induced the differentiation of CD4+T-cell towards Tregs, enhanced Th2 effector, and concomitantly mitigated Th1 and Th17, with polarization of M1 effector macrophages towards their M2 phenotype, and more interestingly enhanced efferocytosis by macrophages indicated Th2 programming ability of MSCs programmed by conjunctional approaches Overall, our study highlights the potential of WJ-MSCs(HYP+APO), as a promising therapeutic strategy for immune-related disorders and underscores the importance of considering MSC apoptosis in optimizing MSCs-based cellular therapy protocols for enhanced therapeutic efficacy in aGvHD.

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“…Both hypoxia and cytokines are known to independently shift MSC metabolism to aerobic glycolysis (108,113); metabolic reconfiguration induced by dual hypoxia and cytokine priming may fuel changes in MSC-EV production and lipid profile related to potency. The protein, particle count, and particle size we observed are within the range seen in similar studies (27,37,44,46,47,(49)(50)(51)(52)(53)(109)(110)(111)(112). The lower purity in our MSC-EV preparations compared to other studies using MSCs (114,115) may be explained by differences in cell manufacturing and MSC-EV isolation and analysis methods.…”

Section: Discussionsupporting

confidence: 82%

High throughput screening of mesenchymal stromal cell morphological response to inflammatory signals for bioreactor-based manufacturing of extracellular vesicles that modulate microglia

Larey,

Spoerer,

Daga

et al. 2023

Preprint

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Due to their immunomodulatory function, mesenchymal stromal cells (MSCs) are a promising therapeutic with the potential to treat neuroinflammation associated with neurodegenerative diseases. This function can be mediated by secreted extracellular vesicles (MSC-EVs). Despite established safety, MSC clinical translation has been unsuccessful due to inconsistent clinical outcomes resulting from functional heterogeneity. Current approaches to mitigate functional heterogeneity include ‘priming’ MSCs with inflammatory signals to enhance function. However, comprehensive evaluation of priming and its effects on MSC-EV function has not been performed. Clinical translation of MSC-EV therapies requires significant manufacturing scale-up, yet few studies have investigated the effects of priming in bioreactors. As MSC morphology has been shown to predict their immunomodulatory function, we screened MSC morphological response to an array of priming signals and evaluated MSC-EV identity and potency in response to priming in flasks and bioreactors. We identified unique priming conditions corresponding to distinct morphologies. These conditions demonstrated a range of MSC-EV preparation quality and lipidome, allowing us to discover a novel MSC-EV manufacturing condition, as well as gain insight into potential mechanisms of MSC-EV microglia modulation. Our novel screening approach and application of priming to MSC-EV bioreactor manufacturing informs refinement of larger-scale manufacturing and enhancement of MSC-EV function.Graphical AbstractHighlightsMSCs morphologically respond to inflammatory priming conditions.Priming ‘hits’ identified from morphological screen increase MSC-EV production.Priming MSCs in bioreactors enhances MSC-EV modulation of microglia.Changes in MSC-EV production and potency reflected by lipid content.First demonstration of effects of priming on MSC production of EVs in a bioreactor.

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Hypoxia preconditioning elicit differential response in tissue-specific MSCs via immunomodulation and exosomal secretion

Cited by 18 publications

References 44 publications

Secretome from human adipose-derived mesenchymal stem cells promotes blood vessel formation and pericyte coverage in experimental skin repair

Secretome from human adipose-derived mesenchymal stem cells promotes blood vessel formation and pericyte coverage in experimental skin repair

Synergistic Hypoxia and Apoptosis Conditioning Unleashes Superior Mesenchymal Stem Cells Efficacy in Acute Graft-versus-Host-Disease

High throughput screening of mesenchymal stromal cell morphological response to inflammatory signals for bioreactor-based manufacturing of extracellular vesicles that modulate microglia

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