bims-mireme 2021-08-15 papers

bims-mireme

Biomed News

on Mitochondria in regenerative medicine

Issue of 2021–08–15
eight papers selected by
Brian Spurlock, The University of North Carolina at Chapel Hill

Extracellular Mitochondrial Components and Effects on Cardiovascular Disease.
New insights into mitophagy and stem cells.
Indispensable Role of HIF-1α Signaling in Post-implantation Survival and Angio-/Vasculogenic Properties of SHED.
Molecular Regulation of Paused Pluripotency in Early Mammalian Embryos and Stem Cells.
Sestrins regulate muscle stem cell metabolic homeostasis.
Roles of mitochondrial unfolded protein response in mammalian stem cells.
Intercellular Transfer of Mitochondria between Senescent Cells through Cytoskeleton-Supported Intercellular Bridges Requires mTOR and CDC42 Signalling.
Human umbilical cord mesenchymal stem cells reduce oxidative damage and apoptosis in diabetic nephropathy by activating Nrf2.

DNA Cell Biol. 2021 Aug 07.

Extracellular Mitochondrial Components and Effects on Cardiovascular Disease.

Yu Xu, Yanhua Yu, Bowen Yang, Jingjiao Hui, Cai Zhang, Hua Fang, Xiaoyun Bian, Min Tao, Yipeng Lu, Zhenglu Shang.

  Besides being powerhouses of the cell, mitochondria released into extracellular space act as intercellular signaling. Mitochondria and their components mediate cell-to-cell communication in free form or embedded in a carrier. The pathogenesis of cardiovascular disease is complex, which shows close relationship with inflammation and metabolic abnormalities. Since mitochondria sustain optimal function of the heart, extracellular mitochondria are emerging as a key regulator in the development of cardiovascular disease. In this review, we provide recent findings in the presence and forms of mitochondria transfer between cells, as well as the effects of these mitochondria on vascular inflammation and ischemic myocardium. Mitochondrial transplantation is a novel treatment paradigm for patients suffering from acute cardiovascular accident and challenges the traditional methods of mitochondria isolation.

Keywords:  extracellular vesicles; free circulating mitochondria DNA; inflammation; mitochondria; mitochondrial transplantation

DOI:  https://doi.org/10.1089/dna.2021.0087
Stem Cell Res Ther. 2021 Aug 11. 12(1): 452

New insights into mitophagy and stem cells.

Qingyin Lin, Jiaqi Chen, Lifang Gu, Xingang Dan, Cheng Zhang, Yanzhou Yang.

  Mitophagy is a specific autophagic phenomenon in which damaged or redundant mitochondria are selectively cleared by autophagic lysosomes. A decrease in mitophagy can accelerate the aging process. Mitophagy is related to health and longevity and is the key to protecting stem cells from metabolic stress damage. Mitophagy decreases the metabolic level of stem cells by clearing active mitochondria, so mitophagy is becoming increasingly necessary to maintain the regenerative capacity of old stem cells. Stem cell senescence is the core problem of tissue aging, and tissue aging occurs not only in stem cells but also in transport amplifying cell chambers and the stem cell environment. The loss of the autophagic ability of stem cells can cause the accumulation of mitochondria and the activation of the metabolic state as well as damage the self-renewal ability and regeneration potential of stem cells. However, the claim remains controversial. Mitophagy is an important survival strategy against nutrient deficiency and starvation, and mitochondrial function and integrity may affect the viability, proliferation and differentiation potential, and longevity of normal stem cells. Mitophagy can affect the health and longevity of the human body, so the number of studies in this field has increased, but the mechanism by which mitophagy participates in stem cell development is still not fully understood. This review describes the potential significance of mitophagy in stem cell developmental processes, such as self-renewal, differentiation and aging. Through this work, we discovered the role and mechanism of mitophagy in different types of stem cells, identified novel targets for killing cancer stem cells and curing cancer, and provided new insights for future research in this field.

Keywords:  Autophagy; Cancer stem cells; Mitochondria; Mitophagy; Stem cells

DOI:  https://doi.org/10.1186/s13287-021-02520-5
Front Cell Dev Biol. 2021 ;9 655073

Indispensable Role of HIF-1α Signaling in Post-implantation Survival and Angio-/Vasculogenic Properties of SHED.

Yuanyuan Han, Qixin Chen, Lili Zhang, Waruna Lakmal Dissanayaka.

   Objectives: Post-implantation survival and timely vascularization of stem-cell based constructs are critical factors in achieving successful outcomes in tissue regeneration approaches. Hypoxia inducible factor-1α (HIF-1α) is known to mediate adaptive functions to ischemic stress in many different cell types. The current study aimed to explore the role of HIF-1α in post-implantation survival and angio-/vasculogenesis of stem cells from human exfoliated deciduous teeth (SHED).
Methods: HIF-1α in SHED was suppressed using siRNA or chemical inhibitor (YC-1) and used in Matrigel plug assay conducted on severe combined immunodeficient mice. The plugs were retrieved on day 3 or 7 post-injection and analyzed for hypoxia status, ki67 expression, DNA fragmentation (TUNEL), cellularity, and vascularization by histology and immunohistochemistry for CD31, HIF-1α, pyruvate dehydrogenase kinase-1 (PDK1), hexokinase 2 (HK2), and glucose transporter 1 (Glut1). Cell viability of HIF-1α silenced SHED under different stress conditions (hypoxia, H2O2, and low glucose) in vitro was measured by CCK-8 assay. CM-H2DCFDA and MitoSOX Red were used to detect cellular and mitochondrial reactive oxygen species (ROS) levels, respectively. PDK1, HK2, and Glut1 expression were measured by western blotting and immunofluorescence. Secretory protein levels of vascular endothelial growth factor (VEGF) and the respective paracrine effects on endothelial cell proliferation and migration were detected by ELISA, CCK-8 assay, and trans-well assay, respectively.
Results: Histological analysis of Matrigel plugs showed significantly reduced cell survival in HIF-1α silenced or chemically inhibited SHED groups, which could be attributed to diminished metabolic adaptations as shown by decreased PDK1, HK2, and Glut1 expression. HIF-1α inhibition in SHED also resulted in significantly low blood vessel formation as observed by a low number of perfused and non-perfused vessels of human or mouse CD31 origin. The viability of HIF-1α silenced SHED was significantly affected under hypoxia, H2O2, and low-glucose conditions in vitro, which was reflected in increased cytoplasmic and mitochondrial ROS levels. Significantly reduced levels of VEGF in HIF-1α silenced SHED resulted in decreased paracrine angiogenic effects as shown by low proliferation and migration of endothelial cells.
Conclusion: HIF-1α plays an indispensable role in post-implantation survival and angio-/vasculogenic properties of SHED by maintaining ROS homeostasis, inducing metabolic adaptations, and VEGF secretion.

Keywords:  HIF-1α; cell metabolism; dental stem cells; post-implantation survival; redox balance; regenerative medicine

DOI:  https://doi.org/10.3389/fcell.2021.655073
Front Cell Dev Biol. 2021 ;9 708318

Molecular Regulation of Paused Pluripotency in Early Mammalian Embryos and Stem Cells.

Vera A van der Weijden, Aydan Bulut-Karslioglu.

  The energetically costly mammalian investment in gestation and lactation requires plentiful nutritional sources and thus links the environmental conditions to reproductive success. Flexibility in adjusting developmental timing enhances chances of survival in adverse conditions. Over 130 mammalian species can reversibly pause early embryonic development by switching to a near dormant state that can be sustained for months, a phenomenon called embryonic diapause. Lineage-specific cells are retained during diapause, and they proliferate and differentiate upon activation. Studying diapause thus reveals principles of pluripotency and dormancy and is not only relevant for development, but also for regeneration and cancer. In this review, we focus on the molecular regulation of diapause in early mammalian embryos and relate it to maintenance of potency in stem cells in vitro. Diapause is established and maintained by active rewiring of the embryonic metabolome, epigenome, and gene expression in communication with maternal tissues. Herein, we particularly discuss factors required at distinct stages of diapause to induce, maintain, and terminate dormancy.

Keywords:  dormancy; embryonic diapause; metabolism; miRNA; pluripotency; signaling pathways; stem cells; transcription

DOI:  https://doi.org/10.3389/fcell.2021.708318
Stem Cell Reports. 2021 Jul 29. pii: S2213-6711(21)00380-5. [Epub ahead of print]

Sestrins regulate muscle stem cell metabolic homeostasis.

Benjamin A Yang, Jesus Castor-Macias, Paula Fraczek, Ashley Cornett, Lemuel A Brown, Myungjin Kim, Susan V Brooks, Isabelle M A Lombaert, Jun Hee Lee, Carlos A Aguilar.

  The health and homeostasis of skeletal muscle are preserved by a population of tissue-resident muscle stem cells (MuSCs) that maintain a state of mitotic and metabolic quiescence in adult tissues. The capacity of MuSCs to preserve the quiescent state declines with aging and metabolic insults, promoting premature activation and stem cell exhaustion. Sestrins are a class of stress-inducible proteins that act as antioxidants and inhibit the activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling complex. Despite these pivotal roles, the role of Sestrins has not been explored in adult stem cells. We show that SESTRIN1,2 loss results in hyperactivation of the mTORC1 complex, increased propensity to enter the cell cycle, and shifts in metabolic flux. Aged SESTRIN1,2 knockout mice exhibited loss of MuSCs and a reduced ability to regenerate injured muscle. These findings demonstrate that Sestrins help maintain metabolic pathways in MuSCs that protect quiescence against aging.

Keywords:  RNA sequencing; aging; mTORC1; metabolism; oxidative stress; reactive oxygen species; regeneration; satellite cells

DOI:  https://doi.org/10.1016/j.stemcr.2021.07.014
World J Stem Cells. 2021 Jul 26. 13(7): 737-752

Roles of mitochondrial unfolded protein response in mammalian stem cells.

Li-Fang Gu, Jia-Qi Chen, Qing-Yin Lin, Yan-Zhou Yang.

  The mitochondrial unfolded protein response (UPRmt) is an evolutionarily conserved adaptive mechanism for improving cell survival under mitochondrial stress. Under physiological and pathological conditions, the UPRmt is the key to maintaining intracellular homeostasis and proteostasis. Important roles of the UPRmt have been demonstrated in a variety of cell types and in cell development, metabolism, and immune processes. UPRmt dysfunction leads to a variety of pathologies, including cancer, inflammation, neurodegenerative disease, metabolic disease, and immune disease. Stem cells have a special ability to self-renew and differentiate into a variety of somatic cells and have been shown to exist in a variety of tissues. These cells are involved in development, tissue renewal, and some disease processes. Although the roles and regulatory mechanisms of the UPRmt in somatic cells have been widely reported, the roles of the UPRmt in stem cells are not fully understood. The roles and functions of the UPRmt depend on stem cell type. Therefore, this paper summarizes the potential significance of the UPRmt in embryonic stem cells, tissue stem cells, tumor stem cells, and induced pluripotent stem cells. The purpose of this review is to provide new insights into stem cell differentiation and tumor pathogenesis.

Keywords:  Cancer; Mammals; Mitochondrial unfolded protein response; Stem cells

DOI:  https://doi.org/10.4252/wjsc.v13.i7.737
Oxid Med Cell Longev. 2021 ;2021 6697861

Intercellular Transfer of Mitochondria between Senescent Cells through Cytoskeleton-Supported Intercellular Bridges Requires mTOR and CDC42 Signalling.

Hannah E Walters, Lynne S Cox.

Cellular senescence is a state of irreversible cell proliferation arrest induced by various stressors including telomere attrition, DNA damage, and oncogene induction. While beneficial as an acute response to stress, the accumulation of senescent cells with increasing age is thought to contribute adversely to the development of cancer and a number of other age-related diseases, including neurodegenerative diseases for which there are currently no effective disease-modifying therapies. Non-cell-autonomous effects of senescent cells have been suggested to arise through the SASP, a wide variety of proinflammatory cytokines, chemokines, and exosomes secreted by senescent cells. Here, we report an additional means of cell communication utilised by senescent cells via large numbers of membrane-bound intercellular bridges-or tunnelling nanotubes (TNTs)-containing the cytoskeletal components actin and tubulin, which form direct physical connections between cells. We observe the presence of mitochondria in these TNTs and show organelle transfer through the TNTs to adjacent cells. While transport of individual mitochondria along single TNTs appears by time-lapse studies to be unidirectional, we show by differentially labelled co-culture experiments that organelle transfer through TNTs can occur between different cells of equivalent cell age, but that senescent cells, rather than proliferating cells, appear to be predominant mitochondrial donors. Using small molecule inhibitors, we demonstrate that senescent cell TNTs are dependent on signalling through the mTOR pathway, which we further show is mediated at least in part through the downstream actin-cytoskeleton regulatory factor CDC42. These findings have significant implications for the development of senomodifying therapies, as they highlight the need to account for local direct cell-cell contacts as well as the SASP in order to treat cancer and diseases of ageing in which senescence is a key factor.

DOI: https://doi.org/10.1155/2021/6697861
Stem Cell Res Ther. 2021 Aug 11. 12(1): 450

Human umbilical cord mesenchymal stem cells reduce oxidative damage and apoptosis in diabetic nephropathy by activating Nrf2.

Ping Nie, Xue Bai, Yan Lou, Yuexin Zhu, Shan Jiang, Lina Zhang, Na Tian, Ping Luo, Bing Li.

   BACKGROUND: Mesenchymal stem cells (MSCs) have a therapeutic effect on diabetic nephropathy (DN) but the underlying mechanism remains unclear. This study was conducted to investigate whether human umbilical cord-MSCs (hUCMSCs) can induce oxidative damage and apoptosis by activating Nrf2.
METHODS: We used a type 2 diabetic rat model and a high-glucose and fat-stimulated human glomerular mesangial cell (hGMC) model. Western blotting, RT-qPCR, and TUNEL staining were performed on animal tissues and cultured cells. Nuclear expression of Nrf2 was detected in the renal tissue. Furthermore, Nrf2 siRNA was used to examine the effects of hUCMSCs on hGMCs. Finally, the effect of hUCMSCs on the Nrf2 upstream signalling pathway was investigated.
RESULTS: After treatment with hUCMSCs, Nrf2 showed increased expression and nuclear translocation. After Nrf2-specific knockout in hGMCs, the protective effect of hUCMSCs on apoptosis induced by high-glucose and fat conditions was reduced. Activation of the PI3K signalling pathway may be helpful for ameliorating DN using hUCMSCs.
CONCLUSIONS: hUCMSCs attenuated renal oxidative damage and apoptosis in type 2 diabetes mellitus and Nrf2 activation is one of the important mechanisms of this effect. hUCMSCs show potential as drug targets for DN.

Keywords:  Apoptosis; Diabetic nephropathy; Mesenchymal stem cell; Nrf2; Oxidative damage

DOI:  https://doi.org/10.1186/s13287-021-02447-x