bims-mireme Biomed News
on Mitochondria in regenerative medicine
Issue of 2021–09–12
ten papers selected by
Brian Spurlock, The University of North Carolina at Chapel Hill
  1. Role of Copper on Mitochondrial Function and Metabolism.
  2. Single cell heterogeneity in human pluripotent stem cells.
  3. Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance.
  4. Exogenous mitochondrial transfer and endogenous mitochondrial fission facilitate AML resistance to OxPhos inhibition.
  5. Metabolic nuclear receptors coordinate energy metabolism to regulate Sox9+ hepatocyte fate.
  6. Activation of P53 Via Nutlin-3a Reveals Role for P53 In ROS Signaling During Cardiac Differentiation of hiPSCs.
  7. Interleukin-10 Modulates the Metabolism and Osteogenesis of Human Dental Pulp Stem Cells.
  8. Glucocorticoids regulate mitochondrial fatty acid oxidation in fetal cardiomyocytes.
  9. Oxidative Stress Enhances Autophagy-Mediated Death Of Stem Cells Through Erk1/2 Signaling Pathway - Implications For Neurotransplantations.
  10. Long-Term Hypoxia Maintains a State of Dedifferentiation and Enhanced Stemness in Fetal Cardiovascular Progenitor Cells.
  1. Front Mol Biosci. 2021 ;8 711227
    Role of Copper on Mitochondrial Function and Metabolism.
    Lina M Ruiz, Allan Libedinsky, Alvaro A Elorza.
      Copper is essential for life processes like energy metabolism, reactive oxygen species detoxification, iron uptake, and signaling in eukaryotic organisms. Mitochondria gather copper for the assembly of cuproenzymes such as the respiratory complex IV, cytochrome c oxidase, and the antioxidant enzyme superoxide dismutase 1. In this regard, copper plays a role in mitochondrial function and signaling involving bioenergetics, dynamics, and mitophagy, which affect cell fate by means of metabolic reprogramming. In mammals, copper homeostasis is tightly regulated by the liver. However, cellular copper levels are tissue specific. Copper imbalances, either overload or deficiency, have been associated with many diseases, including anemia, neutropenia, and thrombocytopenia, as well as tumor development and cancer aggressivity. Consistently, new pharmacological developments have been addressed to reduce or exacerbate copper levels as potential cancer therapies. This review goes over the copper source, distribution, cellular uptake, and its role in mitochondrial function, metabolic reprograming, and cancer biology, linking copper metabolism with the field of regenerative medicine and cancer.
    Keywords:  ROS; cancer; copper; differentiation; hematopoietic stem cells (HSCs); metabolic reprograming; mitochondria; proliferation
    DOI:  https://doi.org/10.3389/fmolb.2021.711227
  2. BMB Rep. 2021 Sep 07. pii: 5411. [Epub ahead of print]
    Single cell heterogeneity in human pluripotent stem cells.
    Seungbok Yang, Yoonjae Cho, Jiwon Jang.
      Human pluripotent stem cells (hPSCs) include human embryonic stem cells (hESCs) derived from blastocysts and human induced pluripotent stem cells (hiPSCs) generated from somatic cell reprogramming. Due to their self-renewal ability and pluripotent differentiation potential, hPSCs serve as an excellent experimental platform for human development, disease modeling, drug screening, and cell therapy. Traditionally, hPSCs were considered to form a homogenous population. However, recent advances in single cell technologies revealed a high degree of variability between individual cells within a hPSC population. Different types of heterogeneity can arise by genetic and epigenetic abnormalities associated with long-term in vitro culture and somatic cell reprogramming. These variations initially appear in a rare population of cells. However, some cancer-related variations can confer growth advantages to the affected cells and alter cellular phenotypes, which raises significant concerns in hPSC applications. In contrast, other types of heterogeneity are related to intrinsic features of hPSCs such as asynchronous cell cycle and spatial asymmetry in cell adhesion. A growing body of evidence suggests that hPSCs exploit the intrinsic heterogeneity to produce multiple lineages during differentiation. This idea offers a new concept of pluripotency with single cell heterogeneity as an integral element. Collectively, single cell heterogeneity is Janus-faced in hPSC function and application. Harmful heterogeneity has to be minimized by improving culture conditions and screening methods. However, other heterogeneity that is integral for pluripotency can be utilized to control hPSC proliferation and differentiation.
  3. Nat Commun. 2021 09 06. 12(1): 5270
    Nrf1 promotes heart regeneration and repair by regulating proteostasis and redox balance.
    Miao Cui, Ayhan Atmanli, Maria Gabriela Morales, Wei Tan, Kenian Chen, Xue Xiao, Lin Xu, Ning Liu, Rhonda Bassel-Duby, Eric N Olson.
      Following injury, cells in regenerative tissues have the ability to regrow. The mechanisms whereby regenerating cells adapt to injury-induced stress conditions and activate the regenerative program remain to be defined. Here, using the mammalian neonatal heart regeneration model, we show that Nrf1, a stress-responsive transcription factor encoded by the Nuclear Factor Erythroid 2 Like 1 (Nfe2l1) gene, is activated in regenerating cardiomyocytes. Genetic deletion of Nrf1 prevented regenerating cardiomyocytes from activating a transcriptional program required for heart regeneration. Conversely, Nrf1 overexpression protected the adult mouse heart from ischemia/reperfusion (I/R) injury. Nrf1 also protected human induced pluripotent stem cell-derived cardiomyocytes from doxorubicin-induced cardiotoxicity and other cardiotoxins. The protective function of Nrf1 is mediated by a dual stress response mechanism involving activation of the proteasome and redox balance. Our findings reveal that the adaptive stress response mechanism mediated by Nrf1 is required for neonatal heart regeneration and confers cardioprotection in the adult heart.
    DOI:  https://doi.org/10.1038/s41467-021-25653-w
  4. Blood Adv. 2021 Sep 10. pii: bloodadvances.2020003661. [Epub ahead of print]
    Exogenous mitochondrial transfer and endogenous mitochondrial fission facilitate AML resistance to OxPhos inhibition.
    Kaori Saito, Qi Zhang, Haeun Yang, Kotoko Yamatani, Tomohiko Ai, Vivian Ruvolo, Natalia Baran, Tianyu Cai, Helen Ma, Rodrigo Jacamo, Vinitha Mary Kuruvilla, Junichi Imoto, Sonoko Kinjo, Kazuho Ikeo, Kaori Moriya, Koya Suzuki, Takashi Miida, Yong-Mi Kim, Christopher P Vellano, Michael Andreeff, Joseph R Marszalek, Yoko Tabe, Marina Y Konopleva.
      Acute myeloid leukemia (AML) cells are highly dependent on oxidative phosphorylation (OxPhos) for survival and continually adapt to fluctuations in nutrient and oxygen availability in the bone marrow (BM) microenvironment. We investigated how the BM microenvironment affects the response to OxPhos inhibition in AML by using a novel complex I OxPhos inhibitor, IACS-010759. Cellular adhesion, growth, and apoptosis assays, along with measurements of mtDNA expression and mitochondrial reactive oxygen species generation, indicated that direct interactions with BM stromal cells triggered compensatory activation of mitochondrial respiration and resistance to OxPhos inhibition in AML cells. Mechanistically, OxPhos inhibition induced (1) transfer of mesenchymal stem cell (MSC)-derived mitochondria to AML cells via tunneling nanotubes under direct-contact coculture conditions, and (2) mitochondrial fission with an increase in functional mitochondria and mitophagy in AML cells. Mitochondrial fission is known to enhance cell migration, and we observed mitochondrial transport to the leading edge of protrusions of migrating AML cells toward MSCs by electron microscopy analysis. We further demonstrated that cytarabine, a commonly used antileukemia agent, increased OxPhos inhibition-triggered mitochondrial transfer from MSCs to AML cells. Our findings indicate an important role of exogenous mitochondrial trafficking from BM stromal cells to AML cells as well as endogenous mitochondrial fission and mitophagy in the compensatory adaptation of leukemia cells to energetic stress in the BM microenvironment.
    DOI:  https://doi.org/10.1182/bloodadvances.2020003661
  5. iScience. 2021 Sep 24. 24(9): 103003
    Metabolic nuclear receptors coordinate energy metabolism to regulate Sox9+ hepatocyte fate.
    Shenghui Liu, Dan Qin, Yi Yan, Jiayan Wu, Lihua Meng, Wendong Huang, Liqiang Wang, Xiangmei Chen, Lisheng Zhang.
      Recent research has indicated the adult liver Sox9+ cells located in the portal triads contribute to the physiological maintenance of liver mass and injury repair. However, the physiology and pathology regulation mechanisms of adult liver Sox9+ cells remain unknown. Here, PPARα and FXR bound to the shared site in Sox9 promoter with opposite transcriptional outputs. PPARα activation enhanced the fatty acid β-oxidation, oxidative phosphorylation (OXPHOS), and adenosine triphosphate (ATP) production, thus promoting proliferation and differentiation of Sox9+ hepatocytes along periportal (PP)-perivenous (PV) axis. However, FXR activation increased glycolysis but decreased OXPHOS and ATP production, therefore preventing proliferation of Sox9+ hepatocytes along PP-PV axis by promoting Sox9+ hepatocyte self-renewal. Our research indicates that metabolic nuclear receptors play critical roles in liver progenitor Sox9+ hepatocyte homeostasis to initiate or terminate liver injury-induced cell proliferation and differentiation, suggesting that PPARα and FXR are potential therapeutic targets for modulating liver regeneration.
    Keywords:  Cell biology; Cellular physiology; Human metabolism; Molecular physiology
    DOI:  https://doi.org/10.1016/j.isci.2021.103003
  6. J Stem Cell Rep. 2021 ;pii: 101. [Epub ahead of print]3(1):
    Activation of P53 Via Nutlin-3a Reveals Role for P53 In ROS Signaling During Cardiac Differentiation of hiPSCs.
    Emma B Brandt, Xing Li, Timothy J Nelson.
      Activation of the transcription factor P53 within cancer cells is a well-characterized pathway, whereas the effects of P53 activation during development remain largely unexplored. Previous research has indicated that increased levels of P53 protein during key murine developmental stages cause defects in multiple embryonic tissues, including the heart. These findings were confirmed in several different mouse models of congenital heart defects, but P53 activation in a human system of cardiovascular development is not available. Utilizing human induced pluripotent stem cells (hiPSCs), we characterized the normal levels of P53 during cardiac differentiation and showed that levels of P53 are high in hiPSCs and decrease upon cardiac lineage commitment. We also observed P53 localization changed from mainly cytoplasmic in iPS colonies to the nucleus in the Nkx2-5 + cardiac progenitor stage. Pharmacological-mediated increase of P53 protein levels with the Mdm2 inhibitor Nutlin-3a during early (mesoderm to cardiac mesoderm) stages of cardiogenesis resulted in a sizeable loss of cardiomyocytes due to increased apoptosis and cell cycle arrest. Interestingly, increasing P53 levels did not result in apoptosis at later (cardiac progenitor to beating cardiomyocytes) stages of the cardiac differentiation. These results illustrate the temporal sensitivity to increased P53 levels during cardiogenesis. We conducted RNA-Seq on these cells with or without Nutlin-3a to ascertain transcriptional differences due to increased P53 at the different stages during the differentiation. Our results from the RNA-Seq revealed up-regulation of Sestrins after Nutlin-3a treatment suggesting a new role for P53 in the metabolism of cardiac regeneration.
    Keywords:  Cardiac differentiation; Human induced pluripotent stem cells; P53; Reactive oxygen species
  7. Cell Reprogram. 2021 Sep 03.
    Interleukin-10 Modulates the Metabolism and Osteogenesis of Human Dental Pulp Stem Cells.
    Li Yuan, Hongxia You, Nianhong Qin, Wenxin Zuo.
      The osteogenic differentiation of mesenchymal stem cells (MSCs) is strongly related with the inflammatory microenvironment. The ability of osteogenic differentiation of MSCs is vital for the bone tissue engineering. Interleukin (IL)-10, a well-known anti-inflammatory factor, plays a key role in tissue repair. Dental pulp stem cells (DPSCs), with the advantage of convenience of extraction, are suitable for the bone tissue engineering. Therefore, it is meaning to explore the effects of IL-10 on the osteogenic differentiation of DPSCs. The proliferation activity of DPSCs were evaluated by MTS assay (CellTiter 96® Aqueous One Solution Cell Proliferation Assay [Promega]) and real-time polymerase chain reaction (RT-PCR). The osteogenic differentiation of DPSCs were determined by Alizarin Red staining, RT-PCR, and alkaline phosphatase activity test. The glucose metabolism was detected by Mito Stress test and glycolysis assay. IL-10 (10 or 20 nM) could enhance the osteogenic differentiation of DPSCs and promoted the metabolic switch from glycolysis to oxidative phosphorylation (OXPHOS), whereas IL-10 (5 and 50 nM) has no obvious effects on the osteogenic differentiation of DPSCs. The OXPHOS inhibitor restrained the promotion of osteogenic differentiation induced by IL-10. These findings show that IL-10 can promote the osteogenesis of DPSCs through the activation of OXPHOS, which provides a potential way for enhancing the osteogenic differentiation of DPSCs in bone tissue engineering.
    Keywords:  IL-10; dental pulp stem cell; glucose metabolism; osteogenesis
    DOI:  https://doi.org/10.1089/cell.2021.0044
  8. J Physiol. 2021 Sep 10.
    Glucocorticoids regulate mitochondrial fatty acid oxidation in fetal cardiomyocytes.
    Jessica R Ivy, Roderic N Carter, Jin-Feng Zhao, Charlotte Buckley, Helena Urquijo, Eva A Rog-Zielinska, Emma Panting, Lenka Hrabalkova, Cara Nicholson, Emma J Agnew, Matthew W Kemp, Nicholson N Morton, Sarah J Stock, Caitlin Wyrwoll, Ian G Ganley, Karen E Chapman.
       KEY POINTS: Glucocorticoids are steroid hormones that play a vital role in late pregnancy in maturing fetal organs, including the heart. In fetal cardiomyocytes in culture, glucocorticoids promote mitochondrial fatty acids oxidation, suggesting they facilitate the perinatal switch from carbohydrates to fatty acids as the predominant energy substrate. Administration of a synthetic glucocorticoid in late pregnancy in mice down-regulates the glucocorticoid receptor and interferes with the normal increase in genes involved in fatty acid metabolism in the heart. In a sheep model of preterm birth, antenatal corticosteroids (synthetic glucocorticoid) down-regulates glucocorticoid receptor and the gene encoding PGC-1α, a master regulator of energy metabolism. These experiments suggest that administration of antenatal corticosteroids in anticipation of preterm delivery may interfere with fetal heart maturation by down-regulating the ability to respond to glucocorticoids.
    ABSTRACT: The late gestational rise in glucocorticoids contributes to the structural and functional maturation of the perinatal heart. Here, we hypothesised that glucocorticoid action contributes to the metabolic switch in perinatal cardiomyocytes from carbohydrate to fatty acid oxidation. In primary mouse fetal cardiomyocytes, dexamethasone treatment induced expression of genes involved in fatty acid oxidation and increased mitochondrial oxidation of palmitate, dependent upon glucocorticoid receptor (GR). Dexamethasone did not, however, induce mitophagy or alter the morphology of the mitochondrial network. In vivo, in neonatal mice, dexamethasone treatment induced cardiac expression of fatty acid oxidation genes. However, dexamethasone treatment of pregnant C57Bl/6 mice at embryonic day (E)13.5 or E16.5 failed to induce fatty acid oxidation genes in fetal hearts assessed 24 hours later. Instead, at E17.5, fatty acid oxidation genes were down-regulated by dexamethasone, as was GR itself. PGC-1α, required for glucocorticoid-induced maturation of primary mouse fetal cardiomyocytes in vitro, was also down-regulated in fetal hearts at E17.5, 24 hours after dexamethasone administration. Similarly, following a course of antenatal corticosteroids in a translational sheep model of preterm birth, both GR and PGC-1α were down-regulated in heart. These data suggest endogenous glucocorticoids support the perinatal switch to fatty acid oxidation in cardiomyocytes through changes in gene expression rather than gross changes in mitochondrial volume or mitochondrial turnover. Moreover, our data suggest that treatment with exogenous glucocorticoids may interfere with normal fetal heart maturation, possibly by down-regulating GR. This has implications for clinical use of antenatal corticosteroids when preterm birth is considered a possibility. This article is protected by copyright. All rights reserved.
    Keywords:  antenatal corticosteroids; cardiomyocytes; early-life programming; glucocorticoid; heart; preterm birth
    DOI:  https://doi.org/10.1113/JP281860
  9. Stem Cell Rev Rep. 2021 Sep 06.
    Oxidative Stress Enhances Autophagy-Mediated Death Of Stem Cells Through Erk1/2 Signaling Pathway - Implications For Neurotransplantations.
    Ravi Prakash, Eram Fauzia, Abu Junaid Siddiqui, Santosh Kumar Yadav, Neha Kumari, Atin Singhai, Mohsin Ali Khan, Miroslaw Janowski, Sujit Kumar Bhutia, Syed Shadab Raza.
      Stem cell therapies are becoming increasingly popular solutions for neurological disorders. However, there is a lower survival rate of these cells after transplantation. Oxidative stress is linked to brain damage, and it may also impact transplanted stem cells. To better understand how transplanted cells respond to oxidative stress, the current study used H2O2. We briefly illustrated that exogenous H2O2 treatment exaggerated oxidative stress in the human dental pulp and mesenchymal stem cells. 2',7'-Dichlorofluorescin diacetate (DCFDA), MitoSOX confirms the reactive oxygen species (ROS) involvement, which was remarkably subsided by the ROS inhibitors. The findings showed that H2O2 activates autophagy by enhancing pro-autophagic proteins, Beclin1 and Atg7. Increased LC3II/I expression (which co-localized with lysosomal proteins, LAMP1 and Cathepsin B) showed that H2O2 treatment promoted autophagolysosome formation. In the results, both Beclin1 and Atg7 were observed co-localized in mitochondria, indicating their involvement in mitophagy. The evaluation of Erk1/2 in the presence and absence of Na-Pyruvate, PEG-Catalase, and PD98059 established ROS-Erk1/2 participation in autophagy regulation. Further, these findings showed a link between apoptosis and autophagy. The results conclude that H2O2 acts as a stressor, promoting autophagy and mitophagy in stem cells under oxidative stress. The current study may help understand better cell survival and death approaches for transplanted cells in various neurological diseases. The current study uses human Dental Pulp and Mesenchymal Stem cells to demonstrate the importance of H2O2-driven autophagy in deciding the fate of these cells in an oxidative microenvironment. To summarise, we discovered that exogenous H2O2 treatment causes oxidative stress. Exogenous H2O2  treatment also increased ROS production, especially intracellular H2O2. H2O2 stimulated the ErK1/2 signaling pathway and autophagy. Erk1/2 was found to cause autophagy. Further, the function of mitophagy appeared to be an important factor in the H2O2-induced regulation of these two human stem cell types. In a nutshell, by engaging in autophagy nucleation, maturation, and terminal phase proteins, we elucidated the participation of autophagy in cell dysfunction and death.
    Keywords:  Autophagy; Erk1/2; H2O2; Oxidative Stress; Stroke
    DOI:  https://doi.org/10.1007/s12015-021-10212-z
  10. Int J Mol Sci. 2021 Aug 29. pii: 9382. [Epub ahead of print]22(17):
    Long-Term Hypoxia Maintains a State of Dedifferentiation and Enhanced Stemness in Fetal Cardiovascular Progenitor Cells.
    Cole Knox, Victor Camberos, Lourdes Ceja, Andrea Monteon, Lorelei Hughes, Lawrence Longo, Mary Kearns-Jonker.
      Early-stage mammalian embryos survive within a low oxygen tension environment and develop into fully functional, healthy organisms despite this hypoxic stress. This suggests that hypoxia plays a regulative role in fetal development that influences cell mobilization, differentiation, proliferation, and survival. The long-term hypoxic environment is sustained throughout gestation. Elucidation of the mechanisms by which cardiovascular stem cells survive and thrive under hypoxic conditions would benefit cell-based therapies where stem cell survival is limited in the hypoxic environment of the infarcted heart. The current study addressed the impact of long-term hypoxia on fetal Islet-1+ cardiovascular progenitor cell clones, which were isolated from sheep housed at high altitude. The cells were then cultured in vitro in 1% oxygen and compared with control Islet-1+ cardiovascular progenitor cells maintained at 21% oxygen. RT-PCR, western blotting, flow cytometry, and migration assays evaluated adaptation to long term hypoxia in terms of survival, proliferation, and signaling. Non-canonical Wnt, Notch, AKT, HIF-2α and Yap1 transcripts were induced by hypoxia. The hypoxic niche environment regulates these signaling pathways to sustain the dedifferentiation and survival of fetal cardiovascular progenitor cells.
    Keywords:  Islet-1; cardiovascular progenitor cells; hypoxia; ovine; stemness
    DOI:  https://doi.org/10.3390/ijms22179382
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