bims-mireme 2021-10-24 papers

bims-mireme

Biomed News

on Mitochondria in regenerative medicine

Issue of 2021–10–24
eleven papers selected by
Brian Spurlock, The University of North Carolina at Chapel Hill

Redox Homeostasis and Regulation in Pluripotent Stem Cells: Uniqueness or Versatility?
Mitochondrial Contributions to Hematopoietic Stem Cell Aging.
Neurogenic Potential of the 18-kDa Mitochondrial Translocator Protein (TSPO) in Pluripotent P19 Stem Cells.
The Role of Citrate Transporter INDY in Metabolism and Stem Cell Homeostasis.
Quantitative analysis of mitochondrial morphologies in human induced pluripotent stem cells for Leigh syndrome.
Disease Modeling of Mitochondrial Cardiomyopathy Using Patient-Specific Induced Pluripotent Stem Cells.
Modulation of Inherent Niches in 3D Multicellular MSC Spheroids Reconfigures Metabolism and Enhances Therapeutic Potential.
The metabolic roots of senescence: mechanisms and opportunities for intervention.
Extracorporeal Shock Wave Enhanced Exogenous Mitochondria into Adipose-Derived Mesenchymal Stem Cells and Further Preserved Heart Function in Rat Dilated Cardiomyopathy.
Antioxidant Activity and Anti-Apoptotic Effect of the Small Molecule Procyanidin B1 in Early Mouse Embryonic Development Produced by Somatic Cell Nuclear Transfer.
Lineage-Selective Disturbance of Early Human Hematopoietic Progenitor Cell Differentiation by the Commonly Used Plasticizer Di-2-ethylhexyl Phthalate via Reactive Oxygen Species: Fatty Acid Oxidation Makes the Difference.

Int J Mol Sci. 2021 Oct 11. pii: 10946. [Epub ahead of print]22(20):

Redox Homeostasis and Regulation in Pluripotent Stem Cells: Uniqueness or Versatility?

Julia S Ivanova, Olga G Lyublinskaya.

  Pluripotent stem cells (PSCs) hold great potential both in studies on developmental biology and clinical practice. Mitochondrial metabolism that encompasses pathways that generate ATP and produce ROS significantly differs between PSCs and somatic cells. Correspondingly, for quite a long time it was believed that the redox homeostasis in PSCs is also highly specific due to the hypoxic niche of their origin-within the pre-implantation blastocyst. However, recent research showed that redox parameters of cultivated PSCs have much in common with that of their differentiated progeny cells. Moreover, it has been proven that, similar to somatic cells, maintaining the physiological ROS level is critical for the regulation of PSC identity, proliferation, differentiation, and de-differentiation. In this review, we aimed to summarize the studies of redox metabolism and signaling in PSCs to compare the redox profiles of pluripotent and differentiated somatic cells. We collected evidence that PSCs possess metabolic plasticity and are able to adapt to both hypoxia and normoxia, that pluripotency is not strictly associated with anaerobic conditions, and that cellular redox homeostasis is similar in PSCs and many other somatic cells under in vitro conditions that may be explained by the high conservatism of the redox regulation system.

Keywords:  ROS; differentiation; pluripotent stem cells; proliferation; redox homeostasis; redox metabolism; redox signaling; somatic reprogramming

DOI:  https://doi.org/10.3390/ijms222010946
Int J Mol Sci. 2021 Oct 15. pii: 11117. [Epub ahead of print]22(20):

Mitochondrial Contributions to Hematopoietic Stem Cell Aging.

Claudia Morganti, Keisuke Ito.

  Mitochondrial dysfunction and stem cell exhaustion are two hallmarks of aging. In the hematopoietic system, aging is linked to imbalanced immune response and reduced regenerative capacity in hematopoietic stem cells (HSCs), as well as an increased predisposition to a spectrum of diseases, including myelodysplastic syndrome and acute myeloid leukemia. Myeloid-biased differentiation and loss of polarity are distinct features of aged HSCs, which generally exhibit enhanced mitochondrial oxidative phosphorylation and increased production of reactive oxygen species (ROS), suggesting a direct role for mitochondria in the degenerative process. Here, we provide an overview of current knowledge of the mitochondrial mechanisms that contribute to age-related phenotypes in HSCs. These include mitochondrial ROS production, alteration/activation of mitochondrial metabolism, the quality control pathway of mitochondria, and inflammation. Greater understanding of the key machineries of HSC aging will allow us to identify new therapeutic targets for preventing, delaying, or even reversing aspects of this process.

Keywords:  ROS; aging; hematopoiesis; hematopoietic stem cell; inflammation; mitochondrial metabolism; stem cell exhaustion

DOI:  https://doi.org/10.3390/ijms222011117
Cells. 2021 Oct 17. pii: 2784. [Epub ahead of print]10(10):

Neurogenic Potential of the 18-kDa Mitochondrial Translocator Protein (TSPO) in Pluripotent P19 Stem Cells.

Laura González-Blanco, Juan Carlos Bermejo-Millo, Gabriela Oliveira, Yaiza Potes, Eduardo Antuña, Iván Menéndez-Valle, Ignacio Vega-Naredo, Ana Coto-Montes, Beatriz Caballero.

  The 18-kDa translocator protein (TSPO) is a key mitochondrial target by which different TSPO ligands exert neuroprotective effects. We assayed the neurogenic potential of TSPO to induce the neuronal differentiation of pluripotent P19 stem cells in vitro. We studied changes in cell morphology, cell proliferation, cell death, the cell cycle, mitochondrial functionality, and the levels of pluripotency and neurogenesis of P19 stem cells treated with the TSPO ligand, PK 11195, in comparison to differentiation induced by retinoid acid (RA) and undifferentiated P19 stem cells. We observed that PK 11195 was able to activate the differentiation of P19 stem cells by promoting the development of embryoid bodies. PK 11195 also induced changes in the cell cycle, decreased cell proliferation, and activated cell death. Mitochondrial metabolism was also enhanced by PK 11195, thus increasing the levels of reactive oxygen species, Ca2+, and ATP as well as the mitochondrial membrane potential. Markers of pluripotency and neurogenesis were also altered during the cell differentiation process, as PK 11195 induced the differentiation of P19 stem cells with a high predisposition toward a neuronal linage, compared to cell differentiation induced by RA. Thus, we suggest a relevant neurogenic potential of TSPO along with broad therapeutic implications.

Keywords:  TSPO; mitochondria; neurogenesis; stem cells

DOI:  https://doi.org/10.3390/cells10102784
Metabolites. 2021 Oct 15. pii: 705. [Epub ahead of print]11(10):

The Role of Citrate Transporter INDY in Metabolism and Stem Cell Homeostasis.

Kavitha Kannan, Blanka Rogina.

  I'm Not Dead Yet (Indy) is a fly gene that encodes a homologue of mammalian SLC13A5 plasma membrane citrate transporter. Reducing expression of Indy gene in flies, and its homologues in worms, extends longevity. Indy reduction in flies, worms, mice and rats affects metabolism by regulating the levels of cytoplasmic citrate, inducing a state similar to calorie restriction. Changes include lower lipid levels, increased insulin sensitivity, increased mitochondrial biogenesis, and prevention of weight gain, among others. The INDY protein is predominantly expressed in fly metabolic tissues: the midgut, fat body and oenocytes. Changes in fly midgut metabolism associated with reduced Indy gene activity lead to preserved mitochondrial function and reduced production of reactive oxygen species. All these changes lead to preserved intestinal stem cell homeostasis, which has a key role in maintaining intestinal epithelium function and enhancing fly healthspan and lifespan. Indy gene expression levels change in response to caloric content of the diet, inflammation and aging, suggesting that INDY regulates metabolic adaptation to nutrition or energetic requirements by controlling citrate levels.

Keywords:  Indy; SLC13A5; aging; citrate transporter; intestinal stem cells; longevity gene; metabolism

DOI:  https://doi.org/10.3390/metabo11100705
Stem Cell Res. 2021 Oct 12. pii: S1873-5061(21)00419-0. [Epub ahead of print]57 102572

Quantitative analysis of mitochondrial morphologies in human induced pluripotent stem cells for Leigh syndrome.

Fibi Meshrkey, Ana Cabrera Ayuso, Raj R Rao, Shilpa Iyer.

  Mitochondria are dynamic organelles with wide range of morphologies contributing to regulating different signaling pathways and several cellular functions. Leigh syndrome (LS) is a classic pediatric mitochondrial disorder characterized by complex and variable clinical pathologies, and primarily affects the nervous system during early development. It is important to understand the differences between mitochondrial morphologies in healthy and diseased states so that focused therapies can target the disease during its early stages. In this study, we performed a comprehensive analysis of mitochondrial dynamics in five patient-derived human induced pluripotent stem cells (hiPSCs) containing different mutations associated with LS. Our results suggest that subtle alterations in mitochondrial morphologies are specific to the mtDNA variant. Three out of the five LS-hiPSCs exhibited characteristics consistent with fused mitochondria. To our knowledge, this is the first comprehensive study that quantifies mitochondrial dynamics in hiPSCs specific to mitochondrial disorders. In addition, we observed an overall decrease in mitochondrial membrane potential in all five LS-hiPSCs. A more thorough analysis of the correlations between mitochondrial dynamics, membrane potential dysfunction caused by mutations in the mtDNA in hiPSCs and differentiated derivatives will aid in identifying unique morphological signatures of various mitochondrial disorders during early stages of embryonic development.

Keywords:  Human induced pluripotent stem cells; Leigh syndrome; Mitochondrial disorders; Mitochondrial dynamics; Mitochondrial membrane potential; Mitochondrial morphology

DOI:  https://doi.org/10.1016/j.scr.2021.102572
Biology (Basel). 2021 Sep 29. pii: 981. [Epub ahead of print]10(10):

Disease Modeling of Mitochondrial Cardiomyopathy Using Patient-Specific Induced Pluripotent Stem Cells.

Takeshi Tokuyama, Razan Elfadil Ahmed, Nawin Chanthra, Tatsuya Anzai, Hideki Uosaki.

  Mitochondrial cardiomyopathy (MCM) is characterized as an oxidative phosphorylation disorder of the heart. More than 100 genetic variants in nuclear or mitochondrial DNA have been associated with MCM. However, the underlying molecular mechanisms linking genetic variants to MCM are not fully understood due to the lack of appropriate cellular and animal models. Patient-specific induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs) provide an attractive experimental platform for modeling cardiovascular diseases and predicting drug efficacy to such diseases. Here we introduce the pathological and therapeutic studies of MCM using iPSC-CMs and discuss the questions and latest strategies for research using iPSC-CMs.

Keywords:  iPSC-derived cardiomyocyte; induced pluripotent stem cells (iPSC); mitochondrial cardiomyopathy; mitochondrial disease

DOI:  https://doi.org/10.3390/biology10100981
Cells. 2021 Oct 14. pii: 2747. [Epub ahead of print]10(10):

Modulation of Inherent Niches in 3D Multicellular MSC Spheroids Reconfigures Metabolism and Enhances Therapeutic Potential.

Li-Chi Chen, Hsin-Wen Wang, Chieh-Cheng Huang.

  Multicellular spheroids show three-dimensional (3D) organization with extensive cell-cell and cell-extracellular matrix interactions. Owing to their native tissue-mimicking characteristics, mesenchymal stem cell (MSC) spheroids are considered promising as implantable therapeutics for stem cell therapy. Herein, we aim to further enhance their therapeutic potential by tuning the cultivation parameters and thus the inherent niche of 3D MSC spheroids. Significantly increased expression of multiple pro-regenerative paracrine signaling molecules and immunomodulatory factors by MSCs was observed after optimizing the conditions for spheroid culture. Moreover, these alterations in cellular behaviors may be associated with not only the hypoxic niche developed in the spheroid core but also with the metabolic reconfiguration of MSCs. The present study provides efficient methods for manipulating the therapeutic capacity of 3D MSC spheroids, thus laying solid foundations for future development and clinical application of spheroid-based MSC therapy for regenerative medicine.

Keywords:  3D cell spheroids; cell therapy; immunomodulation; mesenchymal stem cells; metabolic reconfiguration

DOI:  https://doi.org/10.3390/cells10102747
Nat Metab. 2021 Oct;3(10): 1290-1301

The metabolic roots of senescence: mechanisms and opportunities for intervention.

Christopher D Wiley, Judith Campisi.

Cellular senescence entails a permanent proliferative arrest, coupled to multiple phenotypic changes. Among these changes is the release of numerous biologically active molecules collectively known as the senescence-associated secretory phenotype, or SASP. A growing body of literature indicates that both senescence and the SASP are sensitive to cellular and organismal metabolic states, which in turn can drive phenotypes associated with metabolic dysfunction. Here, we review the current literature linking senescence and metabolism, with an eye toward findings at the cellular level, including both metabolic inducers of senescence and alterations in cellular metabolism associated with senescence. Additionally, we consider how interventions that target either metabolism or senescent cells might influence each other and mitigate some of the pro-aging effects of cellular senescence. We conclude that the most effective interventions will likely break a degenerative feedback cycle by which cellular senescence promotes metabolic diseases, which in turn promote senescence.

DOI: https://doi.org/10.1038/s42255-021-00483-8
Biomedicines. 2021 Sep 30. pii: 1362. [Epub ahead of print]9(10):

Extracorporeal Shock Wave Enhanced Exogenous Mitochondria into Adipose-Derived Mesenchymal Stem Cells and Further Preserved Heart Function in Rat Dilated Cardiomyopathy.

Pei-Hsun Sung, Mel S Lee, Han-Tan Chai, John Y Chiang, Yi-Chen Li, Yi-Ching Chu, Chi-Ruei Huang, Hon-Kan Yip.

  This study tested whether extracorporeal shock wave (ECSW) supported-exogenous mitochondria (Mito) into adipose-derived mesenchymal stem cells (ADMSCs) would preserve left-ventricular-ejection-fraction (LVEF) in doxorubicin/12 mg/kg-induced dilated cardiomyopathy (DCM) rat. Adult-male-SD rats were equally categorized into group 1 (sham-control), group 2 (DCM), group 3 (DCM + ECSW/1.5 mJ/mm2 for 140 shots/week × 3 times/since day 14 after DCM induction), group 4 (DCM + ECSW/1.5 mJ/mm2/100 shots-assisted mito delivery (500 μg) into ADMSCs/1.2 × 106 cells, then implanted into LV myocardium day 14 after DCM induction) and group 5 (DCM + ECSW-assisted mito delivery into ADMSCs/1.2 × 106 cells, then implanted into LV, followed by ECSW/1.5 mJ/mm2 for 140 shots/week × 3 times/since day 14 after DCM induction) and euthanized by day 49. Microscopic findings showed mitochondria were abundantly enhanced by ECSW into H9C2 cells. The q-PCR showed a significant increase in relative number of mitDNA in mitochondrial-transferred H9C2 cells than in control group (p < 0.01). The angiogenesis/angiogenesis factors (VEGF/SDF-1α/IG-F1) in HUVECs were significantly progressively increased by a stepwise-increased amount of ECSW energy (0.1/0.25/0.35 mJ/mm2) (all p < 0.001). The 49-day LVEF was highest in group 1 and significantly progressively increased from groups 2 to 5 (all p < 0.0001). Cardiomyocyte size/fibrosis exhibited an opposite pattern of LVEF, whereas cellular/protein levels of angiogenesis factors (VEGF/SDF-1α) in myocardium were significantly progressively increased from groups 1 to 5 (all p < 0.0001). The protein expressions of apoptotic/mitochondrial (cleaved-caspase-3/cleaved-PARP/mitochondrial-Bax/cytosolic-cytochrome-C), fibrotic (p-Smad3/TGF-ß), oxidative-stress (NOX-1/NOX-2) and pressure-overload/heart failure (BNP/ß-MHC) biomarkers exhibited an opposite pattern of LVEF among the five groups (all p < 0.0001). ECSW-assisted mitochondrial-delivery into ADMSCs plus ECSW offered an additional benefit for preserving LVEF in DCM rat.

Keywords:  angiogenesis; dilated cardiomyopathy; exogenous mitochondria delivery; extracorporeal shock wave; left ventricular ejection fraction

DOI:  https://doi.org/10.3390/biomedicines9101362
Molecules. 2021 Oct 12. pii: 6150. [Epub ahead of print]26(20):

Antioxidant Activity and Anti-Apoptotic Effect of the Small Molecule Procyanidin B1 in Early Mouse Embryonic Development Produced by Somatic Cell Nuclear Transfer.

Wei Gao, Tingting Yu, Guomeng Li, Wei Shu, Yongxun Jin, Mingjun Zhang, Xianfeng Yu.

  As an antioxidant, procyanidin B1(PB1) can improve the development of somatic cell nuclear transfer (SCNT) embryos; PB1 reduces the level of oxidative stress (OS) during the in vitro development of SCNT embryos by decreasing the level of reactive oxygen species (ROS) and increasing the level of glutathione (GSH) and mitochondrial membrane potential (MMP). Metabolite hydrogen peroxide (H2O2) produces OS. Catalase (CAT) can degrade hydrogen peroxide so that it produces less toxic water (H2O) and oxygen (O2) in order to reduce the harm caused by H2O2. Therefore, we tested the CAT level in the in vitro development of SCNT embryos; it was found that PB1 can increase the expression of CAT, indicating that PB1 can offset the harm caused by oxidative stress by increasing the level of CAT. Moreover, if H2O2 accumulates excessively, it produces radical-(HO-) through Fe2+/3+ and damage to DNA. The damage caused to the DNA is mainly repaired by the protein encoded by the DNA damage repair gene. Therefore, we tested the expression of the DNA damage repair gene, OGG1. It was found that PB1 can increase the expression of OGG1 and increase the expression of protein. Through the above test, we proved that PB1 can improve the repairability of DNA damage. DNA damage can lead to cell apoptosis; therefore, we also tested the level of apoptosis of blastocysts, and we found that PB1 reduced the level of apoptosis. In summary, our results show that PB1 reduces the accumulation of H2O2 by decreasing the level of OS during the in vitro development of SCNT embryos and improves the repairability of DNA damage to reduce cell apoptosis. Our results have important significance for the improvement of the development of SCNT embryos in vitro and provide important reference significance for diseases that can be treated using SCNT technology.

Keywords:  SCNT; embryo; mouse; procyanidin B1; reactive oxygen species

DOI:  https://doi.org/10.3390/molecules26206150
Cells. 2021 Oct 09. pii: 2703. [Epub ahead of print]10(10):

Lineage-Selective Disturbance of Early Human Hematopoietic Progenitor Cell Differentiation by the Commonly Used Plasticizer Di-2-ethylhexyl Phthalate via Reactive Oxygen Species: Fatty Acid Oxidation Makes the Difference.

Lars Kaiser, Isabel Quint, René Csuk, Manfred Jung, Hans-Peter Deigner.

  Exposure to ubiquitous endocrine-disrupting chemicals (EDCs) is a major public health concern. We analyzed the physiological impact of the EDC, di-2-ethylhexyl phthalate (DEHP), and found that its metabolite, mono-2-ethylhexyl phthalate (MEHP), had significant adverse effects on myeloid hematopoiesis at environmentally relevant concentrations. An analysis of the underlying mechanism revealed that MEHP promotes increases in reactive oxygen species (ROS) by reducing the activity of superoxide dismutase in all lineages, possibly via its actions at the aryl hydrocarbon receptor. This leads to a metabolic shift away from glycolysis toward the pentose phosphate pathway and ultimately results in the death of hematopoietic cells that rely on glycolysis for energy production. By contrast, cells that utilize fatty acid oxidation for energy production are not susceptible to this outcome due to their capacity to uncouple ATP production. These responses were also detected in non-hematopoietic cells exposed to alternate inducers of ROS.

Keywords:  ROS quenching; di-2-ethylhexyl phthalate; endocrine-disrupting compounds; fatty acid oxidation; hematopoiesis; hematopoietic stem and progenitor cells; hematotoxicity; mono-2-ethylhexyl phthalate; reactive oxygen species

DOI:  https://doi.org/10.3390/cells10102703