Modulating autophagy in mesenchymal stem cells effectively protects against hypoxia- or ischemia-induced injury

Hu, Chenxia; Zhao, Lingfei; Wu, Daxian; Li, Lanjuan

doi:10.1186/s13287-019-1225-x

Cited by 61 publications

(48 citation statements)

References 119 publications

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“…Identifying the mechanism that regulates the responses of MSCs to external stimuli has important implications in designing optimal expansion and delivery strategies for MSC therapeutic applications (Galipeau & Sensebe, 2018;Yin et al, 2019). MSCs are highly responsive to microenvironmental stimuli arising from biological parameters, for example, immunomodulatory cytokines (Gao et al, 2016;Zhao, Ren, & Han, 2016), biomechanical regulation, for example, culture surface tension or stiffness (Bijonowski et al, 2019;Cesarz, Funnell, Guan, & Tamama, 2016), and physiological modulation, for example, oxygen tension (Hu, Zhao, Wu, & Li, 2019;Peck et al, 2019). Our previous studies have indicated that the significant alterations of MSC aggregates are due to different levels of cortical compaction-induced metabolic reconfiguration rather than hypoxic core within aggregates (Bijonowski et al, 2019;Liu et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Aggregation‐induced integrated stress response rejuvenates culture‐expanded human mesenchymal stem cells

Bijonowski

Yuan

et al. 2020

Biotech & Bioengineering

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Protein homeostasis is critical for cellular function, as loss of homeostasis is attributed to aging and the accumulation of unwanted proteins. Human mesenchymal stem cells (MSCs) have shown promising therapeutic potential due to their impressive abilities to secrete inflammatory modulators, angiogenic, and regenerative cytokines. However, there exists the problem of human MSC expansion with compromised therapeutic quality. Duringin vitro expansion, human MSCs are plated on stiff plastics and undergo culture adaptation, which results in aberrant proliferation, shifts in metabolism, and decreased autophagic activity. It has previously been shown that three‐dimensional (3D) aggregation can reverse some of these alterations by heightening autophagy and recovering the metabolic state back to a naïve phenotype. To further understand the proteostasis in human MSC culture, this study investigated the effects of 3D aggregation on the human MSC proteome to determine the specific pathways altered by aggregation. The 3D aggregates and 2D cultures of human MSCs derived from bone marrow (bMSC) and adipose tissue (ASC) were analyzed along with differentiated human dermal fibroblasts (FB). The proteomics analysis showed the elevated eukaryotic initiation factor 2 pathway and the upregulated activity of the integrated stress response (ISR) in 3D aggregates. Specific protein quantification further determined that bMSC and ASC responded to ISR, while FB did not. 3D aggregation significantly increased the ischemic survival of bMSCs and ASCs. Perturbation of ISR with small molecules salubrinal and GSK2606414 resulted in differential responses of bMSC, ASC, and FB. This study indicates that aggregation‐based preconditioning culture holds the potential for improving the therapeutic efficacy of expanded human MSCs via the establishment of ISR and homeostasis.

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Section: Discussionmentioning

confidence: 99%

Aggregation‐induced integrated stress response rejuvenates culture‐expanded human mesenchymal stem cells

Bijonowski

Yuan

et al. 2020

Biotech & Bioengineering

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“…It has been demonstrated that MSCs cultured under hypoxic condition could improve their regenerative potential in variety of tissues [31,32]. Improved potential of the hypoxia-preconditioned MSCs has been reported for different clinical applications including spinal cord and lung injury, hindlimb ischemia and immune-de cient models due to improving their secretion of reparative factors [33,34], and initiating autophagy [35]. Thus, in this study, to further develop the isolation and culture method without using the MDPSC isolation device for DPSC subsets with high regenerative potential, DPSCs were cultured under stable hypoxic (5%) and pH condition which were con rmed by non-contact oxygen analyzer and pH meter.…”

Section: Discussionmentioning

confidence: 99%

“…The hypoxic condition signi cantly reduces apoptosis of MSCs in vitro [49]. Enhanced survival and retention of hypoxic preconditioned MSCs are reported after injection in a spinal cord injury [50], muscle [51], and a cerebral infarction [35]. The role of HIF-1α in cell viability and anti-apoptosis of MSCs has been suggested [52].…”

Section: Discussionmentioning

confidence: 99%

Characterization of Stable Hypoxia-Preconditioned Dental Pulp Stem Cells: Implication for Pulp Regeneration

Zayed¹,

Iohara²,

Watanabe³

et al. 2020

Preprint

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Background: Dental pulp stem cells (DPSCs) have been developed as a potential source of mesenchymal stem cells (MSCs) for regeneration of dental pulp and other tissues. However, further strategies to isolate highly functional DPSCs beyond the colony-forming methods are required. Our clinical study has demonstrated safety and efficacy of DPSCs isolated by G-CSF-induced mobilization and cultured under normoxia (mobilized DPSCs, MDPSCs) for pulp regeneration. It is well known that the oxygen concentration is closely linked to the maintenance of stemness. Thus, in this investigation, hypoxia-preconditioned DPSCs (hpDPSCs) was characterized to develop and improve the clinical utility for regeneration of dental pulp in endodontics.Methods: Colony-forming DPSCs were isolated and preconditioned with hypoxia in a stable closed cultured system and compared with MDPSCs isolated from the individual dog teeth. We examined the proliferation rate, migration potential, anti-apoptotic activity and gene expression of the stem cell markers and angiogenic/neurotrophic factors. Trophic effects of the conditioned medium (CM) were also evaluated. In addition, the expression of immunomodulatory molecules upon stimulation with IFN-γ were investigated. The pulp regenerative potential and transplantation safety of hpDPSCs were further assessed in pulpectomized teeth in dogs by histological and immunohistochemical analyses and by chemistry of blood and urine. tests Results: hpDPSCs demonstrated higher proliferation rate and expression of a major regulator of oxygen homeostasis, HIF-1α, and a stem cell marker, CXCR-4. The direct migratory activity of hpDPSCs in response to G-CSF was significantly higher than MDPSCs. The CM of hpDPSCs stimulated neurite extension. However, there were no changes in angiogenic, migration and anti-apoptotic activities compared with the CM of MDPSCs. The expression of immunomodulatory gene, PTGE was significantly up-regulated by IFN gamma in hpDPSCs compared with MDPSCs. However, no difference in nitric oxide was observed. The regenerated pulp tissue was quantitatively and qualitatively similar in hpDPSC transplants compared with MDPSC transplants in dog teeth. There was no evidence of toxicity or adverse events of the hpDPSC transplantation Conclusions: These results demonstrated that hpDPSCs improved stem cell properties compared to MDPSCs, suggesting their potential clinical utility for pulp regeneration.

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“…Excessive ROS also cause severe oxidative stress, which can promote DNA damage, endothelial dysfunction and local inflammatory responses. On the basis of ischemia, reperfusion triggers the release of intracellular and extracellular damage-associated molecular pattern molecules (DAMPs), therefore, resulting in the accumulation of inflammatory cells such as monocytes, dendritic cells and so on [5].…”

Section: Introductionmentioning

confidence: 99%

IL-37 Gene Modification Enhances the Protective Effects of Mesenchymal Stromal Cells on Intestinal Ischemia Reperfusion Injury

Kong

et al. 2020

Preprint

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Background: Ischemia reperfusion injury (IRI) is the major cause of intestinal damage in clinic. Although either mesenchymal stromal cells (MSCs) or interleukin 37 (IL-37) showed some beneficial roles to ameliorate IRI, their effects are limited. In this study, the protective effects of IL-37 gene-modified MSCs (IL-37-MSCs) for better prevention of intestinal IRI are investigated.Methods: Intestinal IRI model was established by occluding the superior mesenteric artery for 30min and then reperfusing for 72 hours in rats. Forty adult male SD rats were randomly divided into sham control, IL-37-MSC-treated, MSC-treated, recombinant IL-37 (rIL-37)-treated and untreated groups. Intestinal damage was assessed by H&E staining. The levels of gut barrier function factors (diamine oxidase and D-Lactate) and inflammation reactivity cytokine IL-1β were assayed by ELISA. The expressions of tissue damage-related NLRP3 inflammasome and relative proteins including clevead caspase-1, IL-1β and IL-18 were detected by western blot. As downstream of IL-1β and IL-18, the mRNA levels of proinflammatory mediators IL-6 and TNF-α were determined by qPCR. Data were analyzed by one-way analysis of variance among groups.Results: IL-37-MSCs were able to migrate to the damaged tissue and significantly inhibit intestinal IRI. As compared with MSCs or rIL-37 monotherapy group, IL-37-MSC treatment not only improved gut barrier function but also decreased local and systemic inflammation reactivity cytokine IL-1β level in IRI rats. In addition, tissue damage-related NLRP3 and relative proteins (cleaved caspase-1, IL-1β and 4 IL-18) were significantly decreased in IRI rats treated with IL-37-MSCs. Furthermore, IL-1β and IL-18 related proinflammatory mediators IL-6 and TNF-α mRNA expressions were markedly decreased following IL-37-MSC treatment.Conclusion: The results suggest that IL-37 gene modification significantly enhance the protective effects of MSCs against intestinal IRI. In addition, NLRP3-related signaling pathways could be associated with IL-37-MSC mediated protection.

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Modulating autophagy in mesenchymal stem cells effectively protects against hypoxia- or ischemia-induced injury

Cited by 61 publications

References 119 publications

Aggregation‐induced integrated stress response rejuvenates culture‐expanded human mesenchymal stem cells

Aggregation‐induced integrated stress response rejuvenates culture‐expanded human mesenchymal stem cells

Characterization of Stable Hypoxia-Preconditioned Dental Pulp Stem Cells: Implication for Pulp Regeneration

IL-37 Gene Modification Enhances the Protective Effects of Mesenchymal Stromal Cells on Intestinal Ischemia Reperfusion Injury

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