bims-mireme 2021-10-03 papers

bims-mireme

Biomed News

on Mitochondria in regenerative medicine

Issue of 2021–10–03
fourteen papers selected by
Brian Spurlock, The University of North Carolina at Chapel Hill

Oxygen as a Master Regulator of Human Pluripotent Stem Cell Function and Metabolism.
Mitochondrial Biogenesis, Mitochondrial Dynamics, and Mitophagy in the Maturation of Cardiomyocytes.
Hypoxia conditioned mesenchymal stem cells in tissue regeneration application.
Upregulation of mitochondrial dynamics is responsible for osteogenic differentiation of mesenchymal stem cells cultured on self-mineralized collagen membranes.
Hypoxic postconditioning promotes neurogenesis by modulating the metabolism of neural stem cells after cerebral ischemia.
Utilization of Human Samples for Assessment of Mitochondrial Bioenergetics: Gold Standards, Limitations, and Future Perspectives.
Uncovering the Metabolic and Stress Responses of Human Embryonic Stem Cells to FTH1 Gene Silencing.
MicroRNAs as Factors in Bidirectional Crosstalk Between Mitochondria and the Nucleus During Cellular Senescence.
CRISPR-Cas9 correction of OPA1 c.1334G>A: p.R445H restores mitochondrial homeostasis in dominant optic atrophy patient-derived iPSCs.
Antioxidant Effects of Caffeic Acid Lead to Protection of Drosophila Intestinal Stem Cell Aging.
Autophagy, Mesenchymal Stem Cell Differentiation, and Secretion.
Stemness of Human Pluripotent Cells: Hypoxia-Like Response Induced by Low Nitric Oxide.
Biophysical Modulation of the Mitochondrial Metabolism and Redox in Bone Homeostasis and Osteoporosis: How Biophysics Converts into Bioenergetics.
Tonsil-derived mesenchymal stem cells incorporated in reactive oxygen species-releasing hydrogel promote bone formation by increasing the translocation of cell surface GRP78.

J Pers Med. 2021 Sep 10. pii: 905. [Epub ahead of print]11(9):

Oxygen as a Master Regulator of Human Pluripotent Stem Cell Function and Metabolism.

Kinga Nit, Malgorzata Tyszka-Czochara, Sylwia Bobis-Wozowicz.

  Human-induced pluripotent stem cells (hiPSCs) offer numerous possibilities in science and medicine, particularly when combined with precise genome editing methods. hiPSCs are artificially generated equivalents of human embryonic stem cells (hESCs), which possess an unlimited ability to self-renew and the potential to differentiate into any cell type of the human body. Importantly, generating patient-specific hiPSCs enables personalized drug testing or autologous cell therapy upon differentiation into a desired cell line. However, to ensure the highest standard of hiPSC-based biomedical products, their safety and reliability need to be proved. One of the key factors influencing human pluripotent stem cell (hPSC) characteristics and function is oxygen concentration in their microenvironment. In recent years, emerging data have pointed toward the beneficial effect of low oxygen pressure (hypoxia) on both hiPSCs and hESCs. In this review, we examine the state-of-the-art research on the oxygen impact on hiPSC functions and activity with an emphasis on their niche, metabolic state, reprogramming efficiency, and differentiation potential. We also discuss the similarities and differences between PSCs and cancer stem cells (CSCs) with respect to the role of oxygen in both cell types.

Keywords:  cancer stem cells; hypoxia; hypoxia-inducible factors; induced pluripotent stem cells; metabolism; oxygen

DOI:  https://doi.org/10.3390/jpm11090905
Cells. 2021 Sep 18. pii: 2463. [Epub ahead of print]10(9):

Mitochondrial Biogenesis, Mitochondrial Dynamics, and Mitophagy in the Maturation of Cardiomyocytes.

Qianqian Ding, Yanxiang Qi, Suk-Ying Tsang.

  Pluripotent stem cells (PSCs) can undergo unlimited self-renewal and can differentiate into all the cell types present in our body, including cardiomyocytes. Therefore, PSCs can be an excellent source of cardiomyocytes for future regenerative medicine and medical research studies. However, cardiomyocytes obtained from PSC differentiation culture are regarded as immature structurally, electrophysiologically, metabolically, and functionally. Mitochondria are organelles responsible for various cellular functions such as energy metabolism, different catabolic and anabolic processes, calcium fluxes, and various signaling pathways. Cells can respond to cellular needs to increase the mitochondrial mass by mitochondrial biogenesis. On the other hand, cells can also degrade mitochondria through mitophagy. Mitochondria are also dynamic organelles that undergo continuous fusion and fission events. In this review, we aim to summarize previous findings on the changes of mitochondrial biogenesis, mitophagy, and mitochondrial dynamics during the maturation of cardiomyocytes. In addition, we intend to summarize whether changes in these processes would affect the maturation of cardiomyocytes. Lastly, we aim to discuss unanswered questions in the field and to provide insights for the possible strategies of enhancing the maturation of PSC-derived cardiomyocytes.

Keywords:  cardiomyocytes; maturation; mitochondria; mitochondrial biogenesis; mitochondrial dynamics; mitophagy; pluripotent stem cells

DOI:  https://doi.org/10.3390/cells10092463
Tissue Eng Part B Rev. 2021 Sep 26.

Hypoxia conditioned mesenchymal stem cells in tissue regeneration application.

Yanmeng Yang, Eng Hin Lee, Zheng Yang.

Mesenchymal stem cells (MSCs) have been demonstrated as promising cell sources for tissue regeneration due to their capability of self-regeneration, differentiation and immunomodulation. MSCs also exert extensive paracrine effects through release of trophic factors and extracellular vesicles. However, despite extended exploration of MSCs in pre-clinical studies, the results are far from satisfactory due to the poor engraftment and low level of survival after implantation. Hypoxia preconditioning has been proposed as an engineering approach to improve the therapeutic potential of MSCs. During in vitro culture, hypoxic conditions can promote MSC proliferation, survival and migration through various cellular responses to the reduction of oxygen tension. The multilineage differentiation potential of MSCs is altered under hypoxia, with consistent reports of enhanced chondrogenesis. Hypoxia also stimulates the paracrine activities of MSCs and increases the production of secretome both in terms of soluble factors as well as extracellular vesicles. The secretome from hypoxia preconditioned MSCs play important roles in promoting cell proliferation and migration, enhancing angiogenesis while inhibiting apoptosis and inflammation. In this review, we summarise current knowledge of hypoxia-induced changes in MSCs and discuss the application of hypoxia preconditioned MSCs as well as hypoxic secretome in different kinds of disease models.

DOI: https://doi.org/10.1089/ten.TEB.2021.0145
Acta Biomater. 2021 Sep 24. pii: S1742-7061(21)00634-6. [Epub ahead of print]

Upregulation of mitochondrial dynamics is responsible for osteogenic differentiation of mesenchymal stem cells cultured on self-mineralized collagen membranes.

Mei-Chen Wan, Xiao-Yi Tang, Jing Li, Peng Gao, Fu Wang, Min-Juan Shen, Jun-Ting Gu, Franklin Tay, Ji-Hua Chen, Li-Na Niu, Yu-Hong Xiao, Kai Jiao.

  Collagen membranes crosslinked with high molecular weight polyacrylic acid (HPAA) are capable of self-mineralization via in situ intrafibrillar mineralization. These HPAA-crosslinked collagen membranes (HCM) have been shown to promote osteogenic differentiation of mesenchymal stem cells (MSCs) and enhance bone regeneration in vivo. Nevertheless, the biological triggers involved in those processes and the associated mechanisms are not known. Here, we identified the contribution of mitochondrial dynamics in HCM-mediated osteogenic differentiation of MSCs. Mitochondriogenesis markers were significantly upregulated when MSCs were cultured on HCM, committing the MSCs to osteogenic differentiation. The mitochondria fused to form an interconnected mitochondrial network in response to the high energy requirements. Mitochondrial fission in MSCs was also triggered by HCM; fission slightly declined at 14 days to restore the equilibrium in mitochondrial dynamics. Mitophagy, another event that regulates mitochondrial dynamics, occurred actively to remove dysfunctioned mitochondria and isolate damaged mitochondria from the rest of network. The mitophagy level of MSCs was significantly elevated in the presence of HCM. Taken together, the present findings indicate that upregulation of mitochondrial dynamics via mitochondriogenesis, fusion, fission and mitophagy is responsible for HCM-mediated osteogenic differentiation of MSCs. STATEMENT OF SIGNIFICANCE: : High molecular weight polyacrylic acid (HPAA)-crosslinked collagen membrane (HCM) was found to promote in-situ bone regeneration because of it can stimulate osteogenic differentiation of mesenchymal stem cells (MSCs). Nevertheless, the biological triggers involved in those processes and associated mechanisms are not known. This study identifies that activation of mitochondrial dynamics is centrally involved in HCM-mediated osteogenic differentiation of MSCs. The HCM accelerates mitochondriogenesis and regulates homeostasis of the mitochondrial network in response to the increased energy demand for osteogenic differentiation. Concomitantly, mitophagy actively occurs to remove dysfunctioned mitochondria from the rest of the mitochondrial network. Identification of the involvement of mitophagy in HCM-mediated osteogenic differentiation of MSCs opens new vistas in the application of biomimetic mineralization in bone tissue regeneration.

Keywords:  Mitochondrial dynamics; mitophagy; osteogenic differentiation; self-mineralized collagen membranes

DOI:  https://doi.org/10.1016/j.actbio.2021.09.039
Exp Neurol. 2021 Sep 23. pii: S0014-4886(21)00279-X. [Epub ahead of print] 113871

Hypoxic postconditioning promotes neurogenesis by modulating the metabolism of neural stem cells after cerebral ischemia.

Haiyan Li, Sijie Li, Changhong Ren, Chen Gao, Ning Li, Chunxiu Wang, Lin Wang, Wenbo Zhao, Xunming Ji, Kunlin Jin.

  Ischemic stroke is one of the most lethal and severely disabling diseases that seriously affects human health and quality of life. The maintenance of self-renewal and differentiation of neural stem cells are closely related to metabolism. This study aimed to investigate whether hypoxic postconditioning (HPC) could promote neurogenesis after ischemic stroke, and to investigate the role of neuronal stem cell metabolism in HPC-induced neuroprotection. Male C57BL/6 mice were subjected to transient middle cerebral artery occlusion (MCAO), and HPC was performed for 3 h per day. Immunofluorescence staining was used to assess neurogenesis. The cell line NE-4C was used to elucidate the proliferation of neuronal stem cells in 21% O2 or 8% O2. HPC promoted the recovery of neurological function in mice on day 14. HPC promoted neuronal precursor proliferation in the subventricular zone (SVZ) on day 7 and enhanced neuronal precursor migration in the basal ganglia and cortex on day 14. Fatty acid oxidation (FAO) and glycolysis of neural stem cells in the SVZ changed after MCAO with or without HPC. HPC promoted the proliferation of NE-4C stem cells, decreased FAO and increased glycolysis. All these beneficial effects of HPC were ablated by the application of an FAO activator or a glycolysis inhibitor. In conclusion, cerebral ischemia modulated the FAO and glycolysis of neural stem cells. HPC promoted the proliferation and migration of neural stem cells after MCAO, and these effects may be related to the regulation of metabolism, including FAO and glycolysis.

Keywords:  Cerebral ischemia; Hypoxic conditioning; Metabolism; Neurogenesis

DOI:  https://doi.org/10.1016/j.expneurol.2021.113871
Life (Basel). 2021 Sep 10. pii: 949. [Epub ahead of print]11(9):

Utilization of Human Samples for Assessment of Mitochondrial Bioenergetics: Gold Standards, Limitations, and Future Perspectives.

Rebeca Acin-Perez, Cristiane Benincá, Byourak Shabane, Orian S Shirihai, Linsey Stiles.

  Mitochondrial bioenergetic function is a central component of cellular metabolism in health and disease. Mitochondrial oxidative phosphorylation is critical for maintaining energetic homeostasis, and impairment of mitochondrial function underlies the development and progression of metabolic diseases and aging. However, measurement of mitochondrial bioenergetic function can be challenging in human samples due to limitations in the size of the collected sample. Furthermore, the collection of samples from human cohorts is often spread over multiple days and locations, which makes immediate sample processing and bioenergetics analysis challenging. Therefore, sample selection and choice of tests should be carefully considered. Basic research, clinical trials, and mitochondrial disease diagnosis rely primarily on skeletal muscle samples. However, obtaining skeletal muscle biopsies requires an appropriate clinical setting and specialized personnel, making skeletal muscle a less suitable tissue for certain research studies. Circulating white blood cells and platelets offer a promising primary tissue alternative to biopsies for the study of mitochondrial bioenergetics. Recent advances in frozen respirometry protocols combined with the utilization of minimally invasive and non-invasive samples may provide promise for future mitochondrial research studies in humans. Here we review the human samples commonly used for the measurement of mitochondrial bioenergetics with a focus on the advantages and limitations of each sample.

Keywords:  bioenergetics; fibroblasts; frozen tissue; leukocytes; mitochondria; oxygen consumption; platelets; respirometry; skeletal muscle

DOI:  https://doi.org/10.3390/life11090949
Cells. 2021 Sep 15. pii: 2431. [Epub ahead of print]10(9):

Uncovering the Metabolic and Stress Responses of Human Embryonic Stem Cells to FTH1 Gene Silencing.

Luana Scaramuzzino, Valeria Lucchino, Stefania Scalise, Michela Lo Conte, Clara Zannino, Alessandro Sacco, Flavia Biamonte, Elvira Immacolata Parrotta, Francesco Saverio Costanzo, Giovanni Cuda.

  Embryonic stem cells (ESCs) are pluripotent cells with indefinite self-renewal ability and differentiation properties. To function properly and maintain genomic stability, ESCs need to be endowed with an efficient repair system as well as effective redox homeostasis. In this study, we investigated different aspects involved in ESCs' response to iron accumulation following stable knockdown of the ferritin heavy chain (FTH1) gene, which encodes for a major iron storage protein with ferroxidase activity. Experimental findings highlight unexpected and, to a certain extent, paradoxical results. If on one hand FTH1 silencing does not correlate with increased ROS production nor with changes in the redox status, strengthening the concept that hESCs are extremely resistant and, to a certain extent, even refractory to intracellular iron imbalance, on the other, the differentiation potential of hESCs seems to be affected and apoptosis is observed. Interestingly, we found that FTH1 silencing is accompanied by a significant activation of the nuclear factor (erythroid-derived-2)-like 2 (Nrf2) signaling pathway and pentose phosphate pathway (PPP), which crosstalk in driving hESCs antioxidant cascade events. These findings shed new light on how hESCs perform under oxidative stress, dissecting the molecular mechanisms through which Nrf2, in combination with PPP, counteracts oxidative injury triggered by FTH1 knockdown.

Keywords:  FTH1; Nrf2; human embryonic stem cells (hESCs); metabolic rerouting; oxidative stress; redox regulation

DOI:  https://doi.org/10.3390/cells10092431
Front Physiol. 2021 ;12 734976

MicroRNAs as Factors in Bidirectional Crosstalk Between Mitochondria and the Nucleus During Cellular Senescence.

Chiara Giordani, Andrea Silvestrini, Angelica Giuliani, Fabiola Olivieri, Maria Rita Rippo.

  Mitochondria are essential organelles that generate most of the chemical energy to power the cell through ATP production, thus regulating cell homeostasis. Although mitochondria have their own independent genome, most of the mitochondrial proteins are encoded by nuclear genes. An extensive bidirectional communication network between mitochondria and the nucleus has been discovered, thus making them semi-autonomous organelles. The nucleus-to-mitochondria signaling pathway, called Anterograde Signaling Pathway can be deduced, since the majority of mitochondrial proteins are encoded in the nucleus, less is known about the opposite pathway, the so-called mitochondria-to-nucleus retrograde signaling pathway. Several studies have demonstrated that non-coding RNAs are essential "messengers" of this communication between the nucleus and the mitochondria and that they might have a central role in the coordination of important mitochondrial biological processes. In particular, the finding of numerous miRNAs in mitochondria, also known as mitomiRs, enabled insights into their role in mitochondrial gene transcription. MitomiRs could act as important mediators of this complex crosstalk between the nucleus and the mitochondria. Mitochondrial homeostasis is critical for the physiological processes of the cell. Disruption at any stage in their metabolism, dynamics and bioenergetics could lead to the production of considerable amounts of reactive oxygen species and increased mitochondrial permeability, which are among the hallmarks of cellular senescence. Extensive changes in mitomiR expression and distribution have been demonstrated in senescent cells, those could possibly lead to an alteration in mitochondrial homeostasis. Here, we discuss the emerging putative roles of mitomiRs in the bidirectional communication pathways between mitochondria and the nucleus, with a focus on the senescence-associated mitomiRs.

Keywords:  microRNA; mitochondria; mitomiRs; mitonuclear communication; senescence

DOI:  https://doi.org/10.3389/fphys.2021.734976
Mol Ther Nucleic Acids. 2021 Dec 03. 26 432-443

CRISPR-Cas9 correction of OPA1 c.1334G>A: p.R445H restores mitochondrial homeostasis in dominant optic atrophy patient-derived iPSCs.

Paul E Sladen, Pedro R L Perdigão, Grace Salsbury, Tatiana Novoselova, Jacqueline van der Spuy, J Paul Chapple, Patrick Yu-Wai-Man, Michael E Cheetham.

  Autosomal dominant optic atrophy (DOA) is the most common inherited optic neuropathy in the United Kingdom. DOA has an insidious onset in early childhood, typically presenting with bilateral, central visual loss caused by the preferential loss of retinal ganglion cells. 60%-70% of genetically confirmed DOA cases are associated with variants in OPA1, a ubiquitously expressed GTPase that regulates mitochondrial homeostasis through coordination of inner membrane fusion, maintenance of cristae structure, and regulation of bioenergetic output. Whether genetic correction of OPA1 pathogenic variants can alleviate disease-associated phenotypes remains unknown. Here, we demonstrate generation of patient-derived OPA1 c.1334G>A: p.R445H mutant induced pluripotent stem cells (iPSCs), followed by correction of OPA1 through CRISPR-Cas9-guided homology-directed repair (HDR) and evaluate the effect of OPA1 correction on mitochondrial homeostasis. CRISPR-Cas9 gene editing demonstrated an efficient method of OPA1 correction, with successful gene correction in 57% of isolated iPSCs. Correction of OPA1 restored mitochondrial homeostasis, re-establishing the mitochondrial network and basal respiration and ATP production levels. In addition, correction of OPA1 re-established the levels of wild-type (WT) mitochondrial DNA (mtDNA) and reduced susceptibility to apoptotic stimuli. These data demonstrate that nuclear gene correction can restore mitochondrial homeostasis and improve mtDNA integrity in DOA patient-derived cells carrying an OPA1 variant.

Keywords:  CRISPR; OPA1; apoptosis; bioenergetics; gene correction; gene editing; iPSC; mitochondria; optic atrophy; retinal ganglion cell

DOI:  https://doi.org/10.1016/j.omtn.2021.08.015
Front Cell Dev Biol. 2021 ;9 735483

Antioxidant Effects of Caffeic Acid Lead to Protection of Drosophila Intestinal Stem Cell Aging.

Xiao Sheng, Yuedan Zhu, Juanyu Zhou, La Yan, Gang Du, Zhiming Liu, Haiyang Chen.

  The dysfunction or exhaustion of adult stem cells during aging is closely linked to tissue aging and age-related diseases. Circumventing this aging-related exhaustion of adult stem cells could significantly alleviate the functional decline of organs. Therefore, identifying small molecular compounds that could prevent the age-related decline of stem cell function is a primary goal in anti-aging research. Caffeic acid (CA), a phenolic compound synthesized in plants, offers substantial health benefits for multiple age-related diseases and aging. However, the effects of CA on adult stem cells remain largely unknown. Using the Drosophila midgut as a model, this study showed that oral administration with CA significantly delayed age-associated Drosophila gut dysplasia caused by the dysregulation of intestinal stem cells (ISCs) upon aging. Moreover, administering CA retarded the decline of intestinal functions in aged Drosophila and prevented hyperproliferation of age-associated ISC by suppressing oxidative stress-associated JNK signaling. On the other hand, CA supplementation significantly ameliorated the gut hyperplasia defect and reduced environmentally induced mortality, revealing the positive effects of CA on tolerance to stress responses. Taken together, our findings report a crucial role of CA in delaying age-related changes in ISCs of Drosophila.

Keywords:  aging; antioxidant activity; caffeic acid; gut; intestinal stem cell

DOI:  https://doi.org/10.3389/fcell.2021.735483
Biomedicines. 2021 Sep 07. pii: 1178. [Epub ahead of print]9(9):

Autophagy, Mesenchymal Stem Cell Differentiation, and Secretion.

Mikhail Menshikov, Ekaterina Zubkova, Iuri Stafeev, Yelena Parfyonova.

  Mesenchymal stem cells (MSC) are multipotent cells capable to differentiate into adipogenic, osteogenic, and chondrogenic directions, possessing immunomodulatory activity and a capability to stimulate angiogenesis. A scope of these features and capabilities makes MSC a significant factor of tissue homeostasis and repair. Among factors determining the fate of MSC, a prominent place belongs to autophagy, which is activated under different conditions including cell starvation, inflammation, oxidative stress, and some others. In addition to supporting cell homeostasis by elimination of protein aggregates, and non-functional and damaged proteins, autophagy is a necessary factor of change in cell phenotype on the process of cell differentiation. In present review, some mechanisms providing participation of autophagy in cell differentiation are discussed.

Keywords:  autophagy; differentiation; immunomodulation; mesenchymal stem cells; signal transduction

DOI:  https://doi.org/10.3390/biomedicines9091178
Antioxidants (Basel). 2021 Sep 02. pii: 1408. [Epub ahead of print]10(9):

Stemness of Human Pluripotent Cells: Hypoxia-Like Response Induced by Low Nitric Oxide.

Estefanía Caballano-Infantes, Irene Díaz, Ana Belén Hitos, Gladys Margot Cahuana, Antonio Martínez-Ruiz, Bárbara Soria-Juan, Rosario Rodríguez-Griñolo, Abdelkrim Hmadcha, Franz Martín, Bernat Soria, Juan R Tejedo, Francisco Javier Bedoya.

  The optimization of conditions to promote the stemness of pluripotent cells in vitro is instrumental for their use in advanced therapies. We show here that exposure of human iPSCs and human ESCs to low concentrations of the chemical NO donor DETA/NO leads to stabilization of hypoxia-inducible factors (HIF-1α and HIF-2α) under normoxia, with this effect being dependent on diminished Pro 402 hydroxylation and decreased degradation by the proteasome. Moreover, the master genes of pluripotency, NANOG and OCT-4, were upregulated. NO also induces a shift in the metabolic profile of PSCs, with an increased expression of hypoxia response genes in glycolysis. Furthermore, a reduction in the mitochondrial membrane potential with lower oxygen consumption and increased expression of mitochondrial fusion regulators, such as DRP1, was observed. The results reported here indicate that NO mimics hypoxia response in human PSCs and enhances their stemness properties when cultured under normoxic conditions.

Keywords:  hypoxia; metabolism; nitric oxide; normoxia; pluripotency

DOI:  https://doi.org/10.3390/antiox10091408
Antioxidants (Basel). 2021 Aug 30. pii: 1394. [Epub ahead of print]10(9):

Biophysical Modulation of the Mitochondrial Metabolism and Redox in Bone Homeostasis and Osteoporosis: How Biophysics Converts into Bioenergetics.

Feng-Sheng Wang, Re-Wen Wu, Yu-Shan Chen, Jih-Yang Ko, Holger Jahr, Wei-Shiung Lian.

  Bone-forming cells build mineralized microstructure and couple with bone-resorbing cells, harmonizing bone mineral acquisition, and remodeling to maintain bone mass homeostasis. Mitochondrial glycolysis and oxidative phosphorylation pathways together with ROS generation meet the energy requirement for bone-forming cell growth and differentiation, respectively. Moderate mechanical stimulations, such as weight loading, physical activity, ultrasound, vibration, and electromagnetic field stimulation, etc., are advantageous to bone-forming cell activity, promoting bone anabolism to compromise osteoporosis development. A plethora of molecules, including ion channels, integrins, focal adhesion kinases, and myokines, are mechanosensitive and transduce mechanical stimuli into intercellular signaling, regulating growth, mineralized extracellular matrix biosynthesis, and resorption. Mechanical stimulation changes mitochondrial respiration, biogenesis, dynamics, calcium influx, and redox, whereas mechanical disuse induces mitochondrial dysfunction and oxidative stress, which aggravates bone-forming cell apoptosis, senescence, and dysfunction. The control of the mitochondrial biogenesis activator PGC-1α by NAD+-dependent deacetylase sirtuins or myokine FNDC/irisin or repression of oxidative stress by mitochondrial antioxidant Nrf2 modulates the biophysical stimulation for the promotion of bone integrity. This review sheds light onto the roles of mechanosensitive signaling, mitochondrial dynamics, and antioxidants in mediating the anabolic effects of biophysical stimulation to bone tissue and highlights the remedial potential of mitochondrial biogenesis regulators for osteoporosis.

Keywords:  Fndc5; Irisin; Nrf2; PGC-1α; Sirt3; biophysical stimulation; mechanosensitive; mitochondria biogenesis; osteoblasts; osteoporosis

DOI:  https://doi.org/10.3390/antiox10091394
Biomaterials. 2021 Sep 25. pii: S0142-9612(21)00513-5. [Epub ahead of print]278 121156

Tonsil-derived mesenchymal stem cells incorporated in reactive oxygen species-releasing hydrogel promote bone formation by increasing the translocation of cell surface GRP78.

Da Hyeon Choi, Kyeong Eun Lee, Se-Young Oh, Si Min Lee, Beom Soo Jo, Jue-Yeon Lee, Jong-Chul Park, Yoon Jeong Park, Ki Dong Park, Inho Jo, Yoon Shin Park.

  Controlling the senescence of mesenchymal stem cells (MSCs) is essential for improving the efficacy of MSC-based therapies. Here, a model of MSC senescence was established by replicative subculture in tonsil-derived MSCs (TMSCs) using senescence-associated β-galactosidase, telomere-length related genes, stemness, and mitochondrial metabolism. Using transcriptomic and proteomic analyses, we identified glucose-regulated protein 78 (GRP78) as a unique MSC senescence marker. With increasing cell passage number, GRP78 gradually translocated from the cell surface and cytosol to the (peri)nuclear region of TMSCs. A gelatin-based hydrogel releasing a sustained, low level of reactive oxygen species (ROS-hydrogel) was used to improve TMSC quiescence and self-renewal. TMSCs expressing cell surface-specific GRP78 (csGRP78+), collected by magnetic sorting, showed better stem cell function and higher mitochondrial metabolism than unsorted cells. Implantation of csGRP78+ cells embedded in ROS-hydrogel in rats with calvarial defects resulted in increased bone regeneration. Thus, csGRP78 is a promising biomarker of senescent TMSCs, and the combined use of csGRP78+ cells and ROS-hydrogel improved the regenerative capacity of TMSCs by regulating GRP78 translocation.

Keywords:  Bone regeneration; Cell surface GRP78+; Glucose-regulated protein 78; ROS releasing hydrogel; Senescence; Tonsil-derived mesenchymal stem cells

DOI:  https://doi.org/10.1016/j.biomaterials.2021.121156