Regulation Of Stem Cells Research Articles

A global bibliometric and visual analysis of research on premature ovarian failure: Based on the perspective of stem cells.

Premature ovarian failure (POF), a condition influenced by genetic and immune factors, remains incurable despite years of intensive research and significant efforts. This persisting challenge underscores the urgency to address this escalating health concern. Fortunately, stem cell regenerative medicine has emerged as a promising avenue for developing therapeutic strategies and innovative treatments for POF. Bibliometric analysis, renowned for its objectivity, systematic approach, and comprehensive coverage of a given field, has yet to be applied to the study of stem cell research in POF. This study used CiteSpace software to assess contributions and co-occurrence relationships among various countries/regions, institutes, journals, and authors. This approach also allowed us to identify research hotspots and promising future trends within this field. Additionally, we generated visualizing maps utilizing the Web of Science Core Collection (WOSCC) and PubMed publications. By providing valuable information and references, we aim to enhance the understanding of the challenges involved in translating stem cell regeneration into clinical therapeutic potential for POF. Furthermore, our analysis and findings guide researchers and clinicians, facilitating future collaborative research and clinical intervention efforts.

ARID1B maintains mesenchymal stem cell quiescence via inhibition of BCL11B-mediated non-canonical Activin signaling

ARID1B haploinsufficiency in humans causes Coffin-Siris syndrome, associated with developmental delay, facial dysmorphism, and intellectual disability. The role of ARID1B has been widely studied in neuronal development, but whether it also regulates stem cells remains unknown. Here, we employ scRNA-seq and scATAC-seq to dissect the regulatory functions and mechanisms of ARID1B within mesenchymal stem cells (MSCs) using the mouse incisor model. We reveal that loss of Arid1b in the GLI1+ MSC lineage disturbs MSCs’ quiescence and leads to their proliferation due to the ectopic activation of non-canonical Activin signaling via p-ERK. Furthermore, loss of Arid1b upregulates Bcl11b, which encodes a BAF complex subunit that modulates non-canonical Activin signaling by directly regulating the expression of activin A subunit, Inhba. Reduction of Bcl11b or non-canonical Activin signaling restores the MSC population in Arid1b mutant mice. Notably, we have identified that ARID1B suppresses Bcl11b expression via specific binding to its third intron, unveiling the direct inter-regulatory interactions among BAF subunits in MSCs. Our results demonstrate the vital role of ARID1B as an epigenetic modifier in maintaining MSC homeostasis and reveal its intricate mechanistic regulatory network in vivo, providing novel insights into the linkage between chromatin remodeling and stem cell fate determination.

Targeted Therapy of Tumors and Cancer Stem Cells based on Oxidant-Regulated Redox Pathway and its Mechanism.

A malignant tumor is a frequent and common disease that severely threatens human health. Many mechanisms, such as cell signaling pathway, anti-apoptosis mechanism, cell stemness, metabolism, and cell phenotype, have been studied to explain the reasons for chemotherapy, radioresistance, and tumor recurrences in antitumor treatment. Cancer stem cells (CSCs) are important tumor cell subclasses that can potentially organize and regulate stem cell properties. Growing evidence suggests that CSCs can initiate tumors and constitute a significant factor in metastasis, recurrence, and treatment resistance. The inability to completely target and remove CSCs is a considerable obstacle in tumor treatment. Therefore, drugs and therapeutic strategies that can effectively intervene with CSCs are essential for the treatment of different tumor types. However, the current strategies and efficacy of targeted elimination of CSCs are very limited. Oxidative stress has been recognized to play a crucial role in cancer pathophysiology. Moreover, reactive oxygen species (ROS) production and imbalance of the built-in cellular antioxidant defense system are hallmarks of tumor and cancer etiology. The current paper will focus on the regulation and mechanism behind oxidative stress in tumors and cancer stem cells and its tumor therapy applications. Additionally, the article discusses the role of CSCs in causing tumor treatment resistance and recurrence based on a redox perspective. The study also emphasizes that targeted modulation of oxidative stress in CSCs has great potential in tumor therapy, providing novel prospects for tumor therapy.

Megakaryocytic IGF1 coordinates activation and ferroptosis to safeguard hematopoietic stem cell regeneration after radiation injury.

Hematopoietic stem cell (HSC) regeneration underlies hematopoietic recovery from myelosuppression, which is a life-threatening side effect of cytotoxicity. HSC niche is profoundly disrupted after myelosuppressive injury, while if and how the niche is reshaped and regulates HSC regeneration are poorly understood. A mouse model of radiation injury-induced myelosuppression was built by exposing mice to a sublethal dose of ionizing radiation. The dynamic changes in the number, distribution and functionality of HSCs and megakaryocytes were determined by flow cytometry, immunofluorescence, colony assay and bone marrow transplantation, in combination with transcriptomic analysis. The communication between HSCs and megakaryocytes was determined using a coculture system and adoptive transfer. The signaling mechanism was investigated both in vivo and in vitro, and was consolidated using megakaryocyte-specific knockout mice and transgenic mice. Megakaryocytes become a predominant component of HSC niche and localize closer to HSCs after radiation injury. Meanwhile, transient insulin-like growth factor 1 (IGF1) hypersecretion is predominantly provoked in megakaryocytes after radiation injury, whereas HSCs regenerate paralleling megakaryocytic IGF1 hypersecretion. Mechanistically, HSCs are particularly susceptible to megakaryocytic IGF1 hypersecretion, and mTOR downstream of IGF1 signaling not only promotes activation including proliferation and mitochondrial oxidative metabolism of HSCs, but also inhibits ferritinophagy to restrict HSC ferroptosis. Consequently, the delicate coordination between proliferation, mitochondrial oxidative metabolism and ferroptosis ensures functional HSC expansion after radiation injury. Importantly, punctual IGF1 administration simultaneously promotes HSC regeneration and hematopoietic recovery after radiation injury, representing a superior therapeutic approach for myelosuppression. Our study identifies megakaryocytes as a last line of defense against myelosuppressive injury and megakaryocytic IGF1 as a novel niche signal safeguarding HSC regeneration.

Interleukin 1β receptor blocker (Anakinra) and regenerative stem cell therapy: two novel approaches effectively ameliorating diabetic cardiomyopathy

Diabetic cardiomyopathy (DCM) is a serious common complication of diabetes. Unfortunately, there is no satisfied treatment for those patients and more studies are in critical need to cure them. Therefore, we aimed to carry out our current research to explore the role of two novel therapeutic approaches: one a biological drug aimed to block inflammatory signaling of the IL 1beta (IL1β) axis, namely, anakinra; the other is provision of anti-inflammatory regenerative stem cells. Wistar male rats were allocated into four groups: control group: type 2 diabetes mellitus (DM) induced by 6-week high-fat diet (HFD) followed by a single-dose streptozotocin (STZ) 35 mg/kg i.p., then rats were allocated into: DM: untreated; DM BM-MSCs: received a single dose of BM-MSCs (1 × 106 cell/rat) into rat tail vein; DM-Anak received Anak 0.5 μg/kg/day i.p. for 2 weeks. Both therapeutic approaches improved cardiac performance, fibrosis, and hypertrophy. In addition, blood glucose and insulin resistance decreased, while the antioxidant parameter, nuclear factor erythroid 2–related factor 2 (Nrf2) and interleukin 10 (IL10), and anti-inflammatory agent increased. Furthermore, there is a significant reduction in tumor necrosis factor alpha (TNFα), IL1β, caspase1, macrophage marker CD 11b, inducible nitric oxide synthase (iNOS), and T-cell marker CD 8. Both Anak and BM-MSCs effectively ameliorated inflammatory markers and cardiac performance as compared to non-treated diabetics. Improvement is mostly due to anti-inflammatory, antioxidant, anti-apoptotic properties, and regulation of TNFα/IL1β/caspase1 and Nrf2/IL10 pathways.

Microenvironmental interference with intra-articular stem cell regeneration influences the onset and progression of arthritis.

Studies have indicated that the preservation of joint health and the facilitation of damage recovery are predominantly contingent upon the joint's microenvironment, including cell-cell interactions, the extracellular matrix's composition, and the existence of local growth factors. Mesenchymal stem cells (MSCs), which possess the capacity to self-renew and specialize in many directions, respond to cues from the microenvironment, and aid in the regeneration of bone and cartilage, are crucial to this process. Changes in the microenvironment (such as an increase in inflammatory mediators or the breakdown of the extracellular matrix) in the pathological context of arthritis might interfere with stem cell activation and reduce their ability to regenerate. This paper investigates the potential role of joint microenvironmental variables in promoting or inhibiting the development of arthritis by influencing stem cells' ability to regenerate. The present status of research on stem cell activity in the joint microenvironment is also outlined, and potential directions for developing new treatments for arthritis that make use of these intervention techniques to boost stem cell regenerative potential through altering the intra-articular environment are also investigated. This review's objectives are to investigate these processes, offer fresh perspectives, and offer a solid scientific foundation for the creation of arthritic treatment plans in the future.

Age-related and species-specific methylation changes in the protein-coding marmoset sperm epigenome.

The sperm epigenome is thought to affect the developmental programming of the resulting embryo, influencing health and disease in later life. Age-related methylation changes in the sperm of old fathers may mediate the increased risks for reproductive and offspring medical problems. The impact of paternal age on sperm methylation has been extensively studied in humans and, to a lesser extent, in rodents and cattle. Here, we performed a comparative analysis of paternal age effects on protein-coding genes in the human and marmoset sperm methylomes. The marmoset has gained growing importance as a non-human primate model of aging and age-related diseases. Using reduced representation bisulfite sequencing, we identified age-related differentially methylated transcription start site (ageTSS) regions in 204 marmoset and 27 human genes. The direction of methylation changes was the opposite, increasing with age in marmosets and decreasing in humans. None of the identified ageTSS was differentially methylated in both species. Although the average methylation levels of all TSS regions were highly correlated between marmosets and humans, with the majority of TSS being hypomethylated in sperm, more than 300 protein-coding genes were endowed with species-specifically (hypo)methylated TSS. Several genes of the glycosphingolipid (GSL) biosynthesis pathway, which plays a role in embryonic stem cell differentiation and regulation of development, were hypomethylated (<5%) in human and fully methylated (>95%) in marmoset sperm. The expression levels and patterns of defined sets of GSL genes differed considerably between human and marmoset pre-implantation embryo stages and blastocyst tissues, respectively.

YAP and TAZ differentially regulate postnatal cortical progenitor proliferation and astrocyte differentiation.

WW domain-containing transcription regulator 1 (WWTR1, referred to here as TAZ) and Yes-associated protein (YAP, also known as YAP1) are transcriptional co-activators traditionally studied together as a part of the Hippo pathway, and are best known for their roles in stem cell proliferation and differentiation. Despite their similarities, TAZ and YAP can exert divergent cellular effects by differentially interacting with other signaling pathways that regulate stem cell maintenance or differentiation. In this study, we show in mouse neural stem and progenitor cells (NPCs) that TAZ regulates astrocytic differentiation and maturation, and that TAZ mediates some, but not all, of the effects of bone morphogenetic protein (BMP) signaling on astrocytic development. By contrast, both TAZ and YAP mediate the effects on NPC fate of β1-integrin (ITGB1) and integrin-linked kinase signaling, and these effects are dependent on extracellular matrix cues. These findings demonstrate that TAZ and YAP perform divergent functions in the regulation of astrocyte differentiation, where YAP regulates cell cycle states of astrocytic progenitors and TAZ regulates differentiation and maturation from astrocytic progenitors into astrocytes.

Sympathetic nerve signals: orchestrators of mammary development and stem cell vitality.

The mammary gland is a dynamic organ that undergoes significant changes at multiple stages of postnatal development. Although the roles of systemic hormones and microenvironmental cues in mammary homeostasis have been extensively studied, the influence of neural signals, particularly those from the sympathetic nervous system, remains poorly understood. Here, using a mouse mammary gland model, we delved into the regulatory role of sympathetic nervous signaling in the context of mammary stem cells and mammary development. Our findings revealed that depletion of sympathetic nerve signals results in defective mammary development during puberty, adulthood, and pregnancy, accompanied by a reduction in mammary stem cell number. Through in vitro three-dimensional culture and in vivo transplantation analyses, we demonstrated that the absence of sympathetic nerve signals hinders mammary stem cell self-renewal and regeneration, while activation of sympathetic nervous signaling promotes these capacities. Mechanistically, sympathetic nerve signals orchestrate mammary stem cell activity and mammary development through the ERK signaling pathway. Collectively, our study unveils the crucial roles of sympathetic nerve signals in sustaining mammary development and regulating mammary stem cell activity, offering a novel perspective on the involvement of the nervous system in modulating adult stem cell function and organ development.

Regulation of Myc transcription by an enhancer cluster dedicated to pluripotency and early embryonic expression

MYC plays various roles in pluripotent stem cells, including the promotion of somatic cell reprogramming to pluripotency, the regulation of cell competition and the control of embryonic diapause. However, how Myc expression is regulated in this context remains unknown. The Myc gene lies within a ~ 3-megabase gene desert with multiple cis-regulatory elements. Here we use genomic rearrangements, transgenesis and targeted mutation to analyse Myc regulation in early mouse embryos and pluripotent stem cells. We identify a topologically-associated region that homes enhancers dedicated to Myc transcriptional regulation in stem cells of the pre-implantation and early post-implantation embryo. Within this region, we identify elements exclusively dedicated to Myc regulation in pluripotent cells, with distinct enhancers that sequentially activate during naive and formative pluripotency. Deletion of pluripotency-specific enhancers dampens embryonic stem cell competitive ability. These results identify a topologically defined enhancer cluster dedicated to early embryonic expression and uncover a modular mechanism for the regulation of Myc expression in different states of pluripotency.

HAX1-Overexpression Augments Cardioprotective Efficacy of Stem Cell-Based Therapy Through Mediating Hippo-Yap Signaling

Although stem/progenitor cell therapy shows potential for myocardial infarction repair, enhancing the therapeutic efficacy could be achieved through additional genetic modifications. HCLS1-associated protein X-1 (HAX1) has been identified as a versatile modulator responsible for cardio-protective signaling, while its role in regulating stem cell survival and functionality remains unknown. In this study, we investigated whether HAX1 can augment the protective potential of Sca1+ cardiac stromal cells (CSCs) for myocardial injury. The overexpression of HAX1 significantly increased cell proliferation and conferred enhanced resistance to hypoxia-induced cell death in CSCs. Mechanistically, HAX1 can interact with Mst1 (a prominent conductor of Hippo signal transduction) and inhibit its kinase activity for protein phosphorylation. This inhibition led to enhanced nuclear translocation of Yes-associated protein (YAP) and activation of downstream therapeutic-related genes. Notably, HAX1 overexpression significantly increased the pro-angiogenic potential of CSCs, as demonstrated by elevated expression of vascular endothelial growth factors. Importantly, implantation of HAX1-overexpressing CSCs promoted neovascularization, protected against functional deterioration, and ameliorated cardiac fibrosis in ischemic mouse hearts. In conclusion, HAX1 emerges as a valuable and efficient inducer for enhancing the effectiveness of cardiac stem or progenitor cell therapeutics.Graphical

Aberrant activation of TGF-β/ROCK1 enhances stemness during prostatic stromal hyperplasia

Benign prostatic hyperplasia (BPH) is a multifactorial disease in which abnormal growth factor activation and embryonic reawakening are considered important factors. Here we demonstrated that the aberrant activation of transforming growth factor β (TGF-β)/Rho kinase 1 (ROCK1) increased the stemness of BPH tissue by recruiting mesenchymal stem cells (MSCs), indicating the important role of embryonic reawakening in BPH. When TGF-β/ROCK1 is abnormally activated, MSCs are recruited and differentiate into fibroblasts/myofibroblasts, leading to prostate stromal hyperplasia. Further research showed that inhibition of ROCK1 activation suppressed MSC migration and their potential for stromal differentiation. Collectively, our findings suggest that abnormal activation of TGF-β/ROCK1 regulates stem cell lineage specificity, and the small molecule inhibitor GSK269962A could target ROCK1 and may be a potential treatment for BPH.Graphical

Small extracellular vesicles of organoid-derived human retinal stem cells remodel Müller cell fate via miRNA: A novel remedy for retinal degeneration

Remodeling retinal Müller glial fate, including gliosis inhibition and pro-reprogramming, represents a crucial avenue for treating degenerative retinal diseases. Stem cell transplantation exerts effects on modulating retinal Müller glial fate. However, the optimized stem cell products and the underlying therapeutic mechanisms need to be investigated. In the present study, we found that retinal progenitor cells from human embryonic stem cell-derived retinal organoids (hERO-RPCs) transferred extracellular vesicles (EVs) into Müller cells following subretinal transplantation into RCS rats. Small EVs from hERO-RPCs (hERO-RPC-sEVs) were collected and were found to delay photoreceptor degeneration and protect retinal function in RCS rats. hERO-RPC-sEVs were taken up by Müller cells both in vivo and in vitro, and inhibited gliosis while promoting early dedifferentiation of Müller cells. We further explored the miRNA profiles of hERO-RPC-sEVs, which suggested a functional signature associated with neuroprotection and development, as well as the regulation of stem cell and glial fate. Mechanistically, hERO-RPC-sEVs might regulate the fate of Müller cells by miRNA-mediated nuclear factor I transcription factors B (NFIB) downregulation. Collectively, our findings offer novel mechanistic insights into stem cell therapy and promote the development of EV-centered therapeutic strategies.

Molecular Changes in Immunological Characteristics of Bone Marrow Multipotent Mesenchymal Stromal Cells in Lymphoid Neoplasia.

Immune system and bone marrow stromal cells play an important role in maintaining normal hematopoiesis. Lymphoid neoplasia disturbs not only development of immune cells, but other immune response mechanisms as well. Multipotent mesenchymal stromal cells (MSCs) of the bone marrow are involved in immune response regulation through both intercellular interactions and secretion of various cytokines. In hematological malignancies, the bone marrow stromal microenvironment, including MSCs, is altered. Aim of this study was to describe the differences of MSCs' immunological function in the patients with acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL). In ALL, malignant cells arise from the early precursor cells localized in bone marrow, while in DLBCL they arise from more differentiated B-cells. In this study, only the DLBCL patients without bone marrow involvement were included. Growth parameters, surface marker expression, genes of interest expression, and secretion pattern of bone marrow MSCs from the patients with ALL and DLBCL at the onset of the disease and in remission were studied. MSCs from the healthy donors of corresponding ages were used as controls. It has been shown that concentration of MSCs in the bone marrow of the patients with ALL is reduced at the onset of the disease and is restored upon reaching remission; in the patients with DLBCL this parameter does not change. Proliferative capacity of MSCs did not change in the patients with ALL; however, the cells of the DLBCL patients both at the onset and in remission proliferated significantly faster than those from the donors. Expression of the membrane surface markers and expression of the genes important for differentiation, immunological status maintenance, and cytokine secretion differed significantly in the MSCs of the patients from those of the healthy donors and depended on nosology of the disease. Secretomes of the MSCs varied greatly; a number of proteins associated with immune response regulation, differentiation, and maintenance of hematopoietic stem cells were depleted in the secretomes of the cells from the patients. Lymphoid neoplasia leads to dramatic changes in the functional immunological status of MSCs.

Circadian clock regulation of muscle stem cells and its potential therapeutic targeting

Background: The circadian clock drives daily oscillations of stem cell behaviors. Molecular clock components orchestrate key myogenic properties of muscle stem cells (MuSCs) in muscle regeneration. Recent studies indicate circadian clock involvement in the pathogenesis of Duchene Muscular Dystrophy (DMD) and disease progression. We generated a novel mouse model with Bmal1-mediated clock gain-of-function in satellite cells to explore the effect of genetic clock activation in promoting MuSC regenerative response. Furthermore, our recent discovery of Chlorhexidine (CHX) as a clock-activating molecule with pro-myogenic properties provides a pharmacological tool to probe clock modulation for disease applications. Hypothesis: Genetic and pharmacological activation of the circadian clock may promote regenerative capacity via clock-controlled pro-myogenic mechanisms to mitigate dystrophic disease. Methods: Mice with satellite cell-selective ectopic expression of Bmal1 (BMKI) were subjected to cardiotoxin injury to elicit regenerative response. Muscle regeneration at 3, 7, 14, and 30 days post-injury was interrogated via Pax7 immunostaining to determine satellite cell expansion, embryonic myosin heavy chain for nascent myofiber formation and myogenic gene induction. In parallel, we carried out medicinal chemistry optimization of CHX scaffold that yielded structural derivatives with improved clock-enhancing activities. Their clock-modulatory and pro-myogenic effcacies were determined in primary myoblasts and a pre-clinical DMD model, the mdx mice. Results: Upon injury, Bmal1 knock in (BMKI) mice displayed a prolonged phase of myogenic activation coupled with enhanced neo-myofiber formation during regeneration. Ex vivo culture of primary myoblasts isolated from BMKI mice demonstrated augmented proliferative and myogenic properties. Based on the findings of clock gain-of-function in promoting regenerative myogenesis, we screened CHX analogs for improved clock-enhancing activities and identified a new compound, CM2, with increased effcacy on promoting myogenic differentiation and proliferative growth of C2C12 myoblasts, primary mouse myoblast and dystrophin-deficient myoblasts. Both CHX and CM2 were suffcient to promote nascent myofiber formation in vivo induced by injury. Lastly, direct administration of CHX or CM2 into dystrophic muscle markedly induced regenerative response with up-regulations of myogenic factors and clock components. Studies of these clock-activating compounds in bone marrow-derived microphages revealed significant inhibition of NLRP3 inflammasome activation, suggesting both anti-inflammatory and pro-myogenic mechanisms of pharmacological clock activation may contribute to improved dystrophic pathophysiology in the mdx mice. Conclusions: Through genetic and pharmacological approaches to augment clock function, our study establishes the mechanistic basis for targeting circadian clock to promote muscle regenerative repair. The pro-myogenic and anti-inflammatory actions of clock-enhancing molecules suggest their drug development potentials as novel intervention strategy for dystrophic diseases. Arthur Riggs Diabetes and Metabolism Research Institute Innovative Award, R56AG080294. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Impact of Hindlimb Disuse on Sepsis-Induced Myopathy in Older Adult Mice

BACKGROUND: Sepsis, a life-threatening condition due to an overactive immune response, adversely affects multiple organ systems. Despite its significance of accounting for 40% of total body mass, the skeletal muscle system is considered the forgotten organ system affected by sepsis. In addition to the inflammatory aspects of sepsis, patients in the intensive care unit (ICU) frequently experience prolonged periods of bed rest, which can lead to muscle disuse-induced myopathy characterized by muscle atrophy, weakness, and impaired regenerative capacity. Despite the higher incidence of sepsis in bedridden older adults, most research on sepsis-induced myopathy primarily focuses on younger adults under conditions that do not mimic bed rest. In this study, we simulated the clinical conditions of older adult ICU patients by combining sepsis with hindlimb disuse. Our hypotheses were that the combination of sepsis, disuse, and aging would exacerbate muscle atrophy and weakness, while also reducing the number of regenerative stem cells in muscle tissue. Methods: To investigate the functional and morphological responses of skeletal muscle to sepsis, we conducted experiments on 78-week-old male wild-type C57Bl6 mice. They underwent either cecal ligation and puncture (CLP, n = 17) or Sham (n = 14) surgeries. Four days post-surgery, the animals were allocated to hindlimb suspension (HLS — CLP, n=9; Sham, n=10) or normal ambulation (NA — CLP, n=8; Sham, n=4) for seven days. Terminal experiments were conducted after hindlimb suspension or normal ambulation treatments. We assessed peak force production ex vivo in solei muscles, examined the cross-sectional area (CSA) of relevant hindlimb muscles using immunohistochemistry, and quantified the abundance of stem cells through immunohistochemistry (e.g., PAX7+ cells) in muscle sections. Additionally, we evaluated markers of senescence by measuring the protein abundance of p16 and p53 in hindlimb muscle homogenates. Results: CLP surgery resulted in 50% mortality rate (p&lt;0.05). Percentage body mass loss was as follows: 5.3 ± 4.2 for Sham/NA group, 13.3 ± 5.2 for Sham/HLS group, 7.3 ± 4.4 for CLP/NA group, and 17.7 ± 5.5 for CLP/HLS group. Peak absolute force was significantly lower in Sham/HLS and CLP/HLS compared to Sham/NA (Sham/NA = 277±2.4, Sham/HLS = 189±28.4, CLP/NA = 264±23.0, CLP/HLS = 180±48.9 mN, p&lt;0.05). Mice exposed to CLP/HLS displayed a higher cumulative fiber area at smaller fiber sizes (800 to 1000 μm2) (p&lt;0.05), indicating muscle atrophy. CLP/NA caused a 9.8% reduction in solei muscle mass (p &lt; 0.05), while CLP/HLS led to an additional 30% loss in solei mass (p&lt;0.05). Furthermore, CLP/HLS significantly decreased the number of PAX7+ stem cells by 75% (p&lt;0.05). Notably, p16 was significantly increased in response to CLP/HLS (p&lt;0.05), while no changes were observed in p53 abundance. CONCLUSION: This study demonstrates the role of muscle disuse in exacerbating skeletal muscle functional and morphological abnormalities in older adult septic mice, emphasizing the critical contribution of disuse to the pathophysiology of sepsis-induced myopathy. NIH R21AG072011 to OL. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Comparing the effect of using 2-Mercaptoethanol in the cell culture medium of different cell passages of human mesenchymal stem cells.

Preparing a suitable cell culture medium that supports the biological needs of the growing cells is crucial to enhancing the success rate of any in vitro and in vivo experiments and minimizing undesirable interferences. Mesenchymal stem cells ( MSCs) which are powerful regenerative stem cells require being grown in proper culture media to preserve their stemness and therapeutic properties. MSCs are usually grown in Dulbecco's Modified Eagle low glucose Medium (DMEM low glucose) which contains 5.6 mmol/L of glucose and is supplemented with Fetal Bovine Serum (FBS), antibiotics, and 2-Mercaptoethanol. The addition of 2-Mercaptoethanol to the cell culture medium was proposed long ago and has continued to be used until now. Despite the positive effects of adding 2-Mercaptoethanol in the cell culture medium, its use is still controversial and needs continuous updates to limit its interference with experimental treatments. Herein, we found that 2-Mercaptoethanol is beneficial to enhancing the proliferation and survival of MSCs at higher passage numbers while its effect is negligible for earlier passages. This concise study provides updates regarding the suitable time to add 2-Mercaptoethanol which can minimize its intermeddling with the experimental design and treatments.

Crosstalk between DNA Damage Repair and Metabolic Regulation in Hematopoietic Stem Cells.

Self-renewal and differentiation are two characteristics of hematopoietic stem cells (HSCs). Under steady physiological conditions, most primitive HSCs remain quiescent in the bone marrow (BM). They respond to different stimuli to refresh the blood system. The transition from quiescence to activation is accompanied by major changes in metabolism, a fundamental cellular process in living organisms that produces or consumes energy. Cellular metabolism is now considered to be a key regulator of HSC maintenance. Interestingly, HSCs possess a distinct metabolic profile with a preference for glycolysis rather than oxidative phosphorylation (OXPHOS) for energy production. Byproducts from the cellular metabolism can also damage DNA. To counteract such insults, mammalian cells have evolved a complex and efficient DNA damage repair (DDR) system to eliminate various DNA lesions and guard genomic stability. Given the enormous regenerative potential coupled with the lifetime persistence of HSCs, tight control of HSC genome stability is essential. The intersection of DDR and the HSC metabolism has recently emerged as an area of intense research interest, unraveling the profound connections between genomic stability and cellular energetics. In this brief review, we delve into the interplay between DDR deficiency and the metabolic reprogramming of HSCs, shedding light on the dynamic relationship that governs the fate and functionality of these remarkable stem cells. Understanding the crosstalk between DDR and the cellular metabolism will open a new avenue of research designed to target these interacting pathways for improving HSC function and treating hematologic disorders.

Circadian regulation of cancer stem cells and the tumor microenvironment during metastasis.

The circadian clock regulates daily rhythms of numerous physiological activities through tightly coordinated modulation of gene expression and biochemical functions. Circadian disruption is associated with enhanced tumor formation and metastasis via dysregulation of key biological processes and modulation of cancer stem cells (CSCs) and their specialized microenvironment. Here, we review how the circadian clock influences CSCs and their local tumor niches in the context of different stages of tumor metastasis. Identifying circadian therapeutic targets could facilitate the development of new treatments that leverage circadian modulation to ablate tumor-resident CSCs, inhibit tumor metastasis and enhance response to current therapies.

MiRNAs mediate the impact of smoking on dental pulp stem cells via the p53 pathway.

Cigarette smoke changes the genomic and epigenomic imprint of cells. In this study, we investigated the biological consequences of extended cigarette smoke exposure on dental pulp stem cells (DPSCs) and the potential roles of miRNAs. DPSCs were treated with various doses of cigarette smoke condensate (CSC) for up to 6 weeks. Cell proliferation, survival, migration, and differentiation were evaluated. Cytokine and miRNA expression were profiled. The results showed that extended exposure to CSC significantly impaired the regenerative capacity of the DPSCs. Bioinformatic analysis showed that the cell cycle pathway, cancer pathways (small cell lung cancer, pancreatic, colorectal, and prostate cancer), and pathways for TNF, TGF-β, p53, PI3K-Akt, mTOR, and ErbB signal transduction, were associated with altered miRNA profiles. In particular, 3 miRNAs has-miR-26a-5p, has-miR-26b-5p, and has-miR-29b-3p fine-tune the p53 and cell cycle signaling pathways to regulate DPSC cellular activities. The work indicated that miRNAs are promising targets to modulate stem cell regeneration and understanding miRNA-targeted genes and their associated pathways in smoking individuals have significant implications for disease control and prevention.