Stem Cell Metabolism Research Articles

Glycolysis of Tissue Stem Cells in the Macula Flava of Newborn Vocal Fold

There is growing evidence that the cells in the maculae flavae are tissue stem cells and the maculae flavae are a stem cell niche of the human vocal fold mucosa. This study investigated the metabolic activity, especially glycolysis, of the tissue stem cells in the maculae flavae of the human newborn vocal fold. Three normal human newborn vocal folds obtained from autopsy cases were investigated using immunohistochemistry. Among the three phenotypes of cells (cobblestone-like polygonal cells, vocal fold stellate cell-like cells and fibroblast-like spindle cells) in the newborn maculae flavae, a small number of cobblestone-like polygonal cells strongly expressed glucose transporter-1. All three phenotypes of cells in the newborn maculae flavae expressed glycolytic enzymes (hexokinase II, glyceraldehyde-3-phosphate dehydrogenase and lactate dehydrogenase A). The cells did not express phosphofructokinase-1 (rate-limiting enzyme of regular glucose metabolism pathway) but sparsely express glucose-6-phosphate dehydrogenase (rate-limiting enzyme) indicating the cells relied more on the pentose phosphate pathway. The cells' expression of lactate dehydrogenase A suggests the maculae flavae of the newborn vocal fold is likely to be an anaerobic microenvironment where cells perform anaerobic glycolysis. The present study is consistent with the hypothesis that the tissue stem cells in the maculae flavae of the newborn vocal fold seem to rely more on anaerobic glycolysis, especially by the pentose phosphate pathway, for energy supply. Already at birth, the metabolism of the tissue stem cells in the maculae flavae of the newborn vocal fold is likely to prevent the formation of toxic reactive oxygen species and is likely favorable to maintaining the stemness and undifferentiated states of the tissue stem cells in the stem cell system.

Metabolic Studies in Organoids: Current Applications, Opportunities and Challenges

Organoid technologies represent a major breakthrough in biomedical research since they offer increasingly sophisticated models for studying biological mechanisms supporting human development and disease. Organoids are three-dimensional (3D) physiological in vitro systems that recapitulate the genetic, histological and functional features of the in vivo tissues of origin more accurately than classical cell culture methods. In the last decade, organoids have been derived from various healthy and diseased tissues and used for a wide range of applications in basic and translational research, including (cancer) tissue biology, development, regeneration, disease modeling, precision medicine, gene editing, biobanking and drug screening. Here, we report the current applications of organoid models to study (stem) cell metabolism in several pathophysiological contexts such as cancer and metabolic diseases. More precisely, we discuss the relevance and limitations of these 3D cultures to model and study metabolic (dys)functions associated with hepatic, renal or pancreatic disorders, as well as tumor development and progression. We also describe the use of organoids to understand the dynamic interaction between diet, microbiota and the intestinal epithelium. Finally, this review explores recent methodological improvements in organoid culture that may help to better integrate the influence of microenvironmental conditions in the study of tumor cell metabolic phenotypes.

Deciphering Metabolic Adaptability of Leukemic Stem Cells.

Therapeutic targeting of leukemic stem cells is widely studied to control leukemia. An emerging approach gaining popularity is altering metabolism as a potential therapeutic opportunity. Studies have been carried out on hematopoietic and leukemic stem cells to identify vulnerable pathways without impacting the non-transformed, healthy counterparts. While many metabolic studies have been conducted using stem cells, most have been carried out in vitro or on a larger population of progenitor cells due to challenges imposed by the low frequency of stem cells found in vivo. This creates artifacts in the studies carried out, making it difficult to interpret and correlate the findings to stem cells directly. This review discusses the metabolic difference seen between hematopoietic stem cells and leukemic stem cells across different leukemic models. Moreover, we also shed light on the advancements of metabolic techniques and current limitations and areas for additional research of the field to study stem cell metabolism.

Cells Dynamically Adapt to Surface Geometry by Remodeling Their Focal Adhesions and Actin Cytoskeleton.

Cells probe their environment and adapt their shape accordingly via the organization of focal adhesions and the actin cytoskeleton. In an earlier publication, we described the relationship between cell shape and physiology, for example, shape-induced differentiation, metabolism, and proliferation in mesenchymal stem cells and tenocytes. In this study, we investigated how these cells organize their adhesive machinery over time when exposed to microfabricated surfaces of different topographies and adhesive island geometries. We further examined the reciprocal interaction between stress fiber and focal adhesion formation by pharmacological perturbations. Our results confirm the current literature that spatial organization of adhesive sites determines the ability to form focal adhesions and stress fibers. Therefore, cells on roughened surfaces have smaller focal adhesion and fewer stress fibers. Our results further highlight the importance of integrin-mediated adhesion in the adaptive properties of cells and provide clear links to the development of bioactive materials.

Epigenetics, cell cycle and stem cell metabolism. Formation of insulin-producing cells

Stem cell (SC) differentiation requires a series of chromatin rearrangements to establish cell identity. Posttranslational modifications of histones usually regulate the dynamics of heterochromatin. Histones are subjected to various modifications, such as acetylation, methylation, phosphorylation and ubiquinination, and thus contribute to regulation of chromatin status and transcriptional activity. The chemically stable pattern of methylated histones promotes cellular memory relative to external stimuli, maintaining transcription levels of adaptive genes even after elimination of environmental signals. Chromatin modifications play an important role in the maturation of pancreatic islet cells, the establishment of a secretion pattern that stimulates the regulation of insulin secretion. MicroRNAs, a class of endogenous small noncoding RNAs in eukaryotes, are important regulators of gene expression at the level of posttranscriptional mechanisms. MicroRNAs regulate insulin secretion, pancreatic development, and β-cell differentiation. Pluripotent SCs are characterized by a high rate of proliferation, the ability to self-repair and the potential for differentiation in different cell types. This rapid proliferation is due to a modified cell cycle that allows cells to rapidly transition from DNA synthesis to cell division by reducing the time of gap (G1 and G2) phases. The canonical WNT/β-catenin signaling pathway is characterized as a major driver of cell growth and proliferation. At G1, WNT signaling induces a transition to the S-phase. Compared to their somatic counterparts, pluripotent SCs exhibit a high rate of glycolysis similar to aerobic glycolysis in cancer cells, a phenomenon known as the Warburg effect, which is important for maintaining SC properties. In stem cells, the extracellular influx of Ca2+ into the cytoplasm is mediated mainly by depot-controlled Ca2+ channels. Extracellular calcium has been shown to promote SC proliferation and thus may be involved in transplant therapy.

Influence of Maternal Exercise on Glucose and Lipid Metabolism in Offspring Stem Cells: ENHANCED by Mom.

Recent preclinical data suggest exercise during pregnancy can improve the metabolic phenotype not only of the mother, but of the developing offspring as well. However, investigations in human offspring are lacking. To characterize the effect of maternal aerobic exercise on the metabolic phenotype of the offspring's mesenchymal stem cells (MSCs). Randomized controlled trial. Clinical research facility. Healthy female adults between 18 and 35 years of age and ≤ 16 weeks' gestation. Mothers were randomized into 1 of 2 groups: aerobic exercise (AE, n = 10) or nonexercise control (CTRL, n = 10). The AE group completed 150 minutes of weekly moderate-intensity exercise, according to American College of Sports Medicine guidelines, during pregnancy, whereas controls attended stretching sessions. Following delivery, MSCs were isolated from the umbilical cord of the offspring and metabolic tracer and immunoblotting experiments were completed in the undifferentiated (D0) or myogenically differentiated (D21) state. AE-MSCs at D0 had an elevated fold-change over basal in insulin-stimulated glycogen synthesis and reduced nonoxidized glucose metabolite (NOGM) production (P ≤ 0.05). At D21, AE-MSCs had a significant elevation in glucose partitioning toward oxidation (oxidation/NOGM ratio) compared with CTRL (P ≤ 0.05). Immunoblot analysis revealed elevated complex I expression in the AE-MSCs at D21 (P ≤ 0.05). Basal and palmitate-stimulated lipid metabolism was similar between groups at D0 and D21. These data provide evidence of a programmed metabolic phenotype in human offspring with maternal AE during pregnancy.

Programmed epigenetic risk: Can stress exposures in utero predispose infants to obesity and metabolic diseases?

Dr. Kristen Boyle is an Associate Professor in the Department of Pediatrics Nutrition Section studying the regulation of human stem cell metabolism and phenotype in the context of obesity and diabetes. During her early independent career Dr. Boyle began using primary infant mesenchymal stem cells, derived from umbilical cord tissue, to investigate stem cell phenotype and epigenetic signatures as a model for developmental programming in humans. She discovered that cells from infants born to mothers with obesity have epigenetic and metabolic perturbations similar to adults with established obesity and associated with greater child adiposity. Thus, infant stem cell metabolism may elucidate how some children are at increased risk for developing obesity and diabetes later in life, independent of postnatal lifestyle exposures. Dr. Boyle’s current research program focuses on using these infant cells to understand how various maternal stress exposures, from metabolic disease to environmental toxins, may impact offspring metabolic phenotypes through epigenetic mechanisms. Her work is supported by the American Diabetes Association and the NIDDK. The goal of this research is to help identify which maternal factors may most influence metabolic differences in the cells and children, and to determine which children may be most at risk for developing obesity or diabetes in the future so that we may develop better tools for obesity or diabetes prevention strategies.

Correlation between amino acid metabolism and self-renewal of cancer stem cells: Perspectives in cancer therapy

Cancer stem cells (CSCs) possess self-renewal and differentiation potential, which may be related to recurrence, metastasis, and radiochemotherapy resistance during tumor treatment. Understanding the mechanisms via which CSCs maintain self-renewal may reveal new therapeutic targets for attenuating CSC resistance and extending patient life-span. Recent studies have shown that amino acid metabolism plays an important role in maintaining the self-renewal of CSCs and is involved in regulating their tumorigenicity characteristics. This review summarizes the relationship between CSCs and amino acid metabolism, and discusses the possible mechanisms by which amino acid metabolism regulates CSC characteristics particularly self-renewal, survival and stemness. The ultimate goal is to identify new targets and research directions for elimination of CSCs.

Impairment of Glucose Metabolism and Suppression of Stemness in MCF-7/SC Human Breast Cancer Stem Cells by Nootkatone.

Targeting cancer stem cell metabolism has emerged as a promising therapeutic strategy for cancer treatment. Breast cancer stem cells (BCSCs) exert distinct metabolism machinery, which plays a major role in radiation and multidrug resistance. Therefore, exploring the mechanisms involved in energy utilization of BCSCs could improve the effectiveness of therapeutic strategies aimed at their elimination. This study was conducted to clarify the glucose metabolism machinery and the function of nootkatone, a bioactive component of grapefruit, in regulating glucose metabolism and stemness characteristics in human breast carcinoma MCF-7 stem cells (MCF-7SCs). In vivo experiments, transcriptomic analysis, seahorse XF analysis, MTT assay, Western blotting, mammosphere formation, wound healing, invasion assay, flow cytometric analysis, reverse transcription-quantitative polymerase chain reaction, and in silico docking experiments were performed. MCF-7SCs showed a greater tumorigenic capacity and distinct gene profile with enrichment of the genes involved in stemness and glycolysis signaling pathways compared to parental MCF-7 cells, indicating that MCF-7SCs use glycolysis rather than oxidative phosphorylation (OXPHOS) for their energy supply. Nootkatone impaired glucose metabolism through AMPK activation and reduced the stemness characteristics of MCF-7SCs. In silico docking analysis demonstrated that nootkatone efficiently bound to the active site of AMPK. Therefore, this study indicates that regulation of glucose metabolism through AMPK activation could be an attractive target for BCSCs.

The role of autophagy in the metabolism and differentiation of stem cells

Autophagy is a very well-coordinated intracellular process that maintains cellular homeostasis under basal conditions by removing unnecessary or dysfunctional components through orderly degradation and recycling. Under pathological conditions, defects in autophagy have been linked to various human disorders, including neurodegenerative disorders and cancer. The role of autophagy in stem cell proliferation, differentiation, self-renewal, and senescence is well documented. Additionally, cancer stem cells (CSCs) play an important role in tumorigenesis, metastasis and tumor relapse and several studies have suggested the involvement of autophagy in the maintenance and invasiveness of CSCs. Hence, considering the modulation of autophagy in normal and cancer stems cells as a therapeutic approach can lead to the development or improvement of regenerative and anti-cancer therapies. Accordingly, modulation of autophagy can be regarded as a target for stem cell-based therapy of diseases with abnormal levels of autophagy.This article is focused on understanding the role of autophagy in stem cell homeostasis with an emphasis on the therapeutic potential of targeting autophagy for future therapies.

Functions of Stress-Induced Lipid Droplets in the Nervous System.

Lipid droplets are highly dynamic intracellular organelles that store neutral lipids such as cholesteryl esters and triacylglycerols. They have recently emerged as key stress response components in many different cell types. Lipid droplets in the nervous system are mostly observed in vivo in glia, ependymal cells and microglia. They tend to become more numerous in these cell types and can also form in neurons as a consequence of ageing or stresses involving redox imbalance and lipotoxicity. Abundant lipid droplets are also a characteristic feature of several neurodegenerative diseases. In this minireview, we take a cell-type perspective on recent advances in our understanding of lipid droplet metabolism in glia, neurons and neural stem cells during health and disease. We highlight that a given lipid droplet subfunction, such as triacylglycerol lipolysis, can be physiologically beneficial or harmful to the functions of the nervous system depending upon cellular context. The mechanistic understanding of context-dependent lipid droplet functions in the nervous system is progressing apace, aided by new technologies for probing the lipid droplet proteome and lipidome with single-cell type precision.

MFN2 knockdown promotes osteogenic differentiation of iPSC-MSCs through aerobic glycolysis mediated by the Wnt/\u03b2-catenin signaling pathway

BackgroundMitofusin-2 (MFN2) is a kind of GTPase that participates in the regulation of mitochondrial fusion, which is related to a variety of physiological and pathological processes, including energy metabolism, cell differentiation, and embryonic development. However, it remains unclear whether MFN2 is involved in the metabolism and osteogenic differentiation of mesenchymal stem cells (MSCs).MethodsMFN2 knockdown (MFN2-KD) and MFN2-overexpressing (MFN2-OE) induced pluripotent stem cell-derived mesenchymal stem cells (iPSC-MSCs) were constructed by lentivirus. The commercial kits were utilized to detect the glycolysis and oxidative phosphorylation (OXPHOS) rate. Flow cytometry, Western blot, quantitative real-time polymerase chain reaction (qRT-PCR), RNA-seq, immunofluorescence, and immunoprecipitation were employed for phenotype and molecular mechanism assessment.ResultsWe demonstrated that MFN2 and Wnt/β-catenin signaling pathway regulated glycolysis of iPSC-MSCs. The lack of MFN2 promoted the osteogenic differentiation of iPSC-MSCs, and aerobic glycolysis in the presence of sufficient oxygen, which increased glucose consumption and lactic acid production, as well as the glycolytic enzyme activity and gene expression. Inhibiting the Wnt/β-catenin signaling pathway normalized the enhanced glycolytic rate and osteogenic differentiation of MFN2-KD iPSC-MSCs. MFN2-OE iPSC-MSCs displayed the opposite phenotype.ConclusionsDownregulating MFN2 promotes osteogenic differentiation of iPSC-MSCs through aerobic glycolysis mediated by the Wnt/β-catenin signaling pathway. Our research reveals the new function of MFN2 in regulating the osteogenic differentiation and energy metabolism of MSCs, which will provide a new therapeutic target and theoretical basis for alveolar bone repair and periodontal regenerative treatment.

Trained Immunity Contribution to Autoimmune and Inflammatory Disorders.

A dysregulated immune response toward self-antigens characterizes autoimmune and autoinflammatory (AIF) disorders. Autoantibodies or autoreactive T cells contribute to autoimmune diseases, while autoinflammation results from a hyper-functional innate immune system. Aside from their differences, many studies suggest that monocytes and macrophages (Mo/Ma) significantly contribute to the development of both types of disease. Mo/Ma are innate immune cells that promote an immune-modulatory, pro-inflammatory, or repair response depending on the microenvironment. However, understanding the contribution of these cells to different immune disorders has been difficult due to their high functional and phenotypic plasticity. Several factors can influence the function of Mo/Ma under the landscape of autoimmune/autoinflammatory diseases, such as genetic predisposition, epigenetic changes, or infections. For instance, some vaccines and microorganisms can induce epigenetic changes in Mo/Ma, modifying their functional responses. This phenomenon is known as trained immunity. Trained immunity can be mediated by Mo/Ma and NK cells independently of T and B cell function. It is defined as the altered innate immune response to the same or different microorganisms during a second encounter. The improvement in cell function is related to epigenetic and metabolic changes that modify gene expression. Although the benefits of immune training have been highlighted in a vaccination context, the effects of this type of immune response on autoimmunity and chronic inflammation still remain controversial. Induction of trained immunity reprograms cellular metabolism in hematopoietic stem cells (HSCs), transmitting a memory-like phenotype to the cells. Thus, trained Mo/Ma derived from HSCs typically present a metabolic shift toward glycolysis, which leads to the modification of the chromatin architecture. During trained immunity, the epigenetic changes facilitate the specific gene expression after secondary challenge with other stimuli. Consequently, the enhanced pro-inflammatory response could contribute to developing or maintaining autoimmune/autoinflammatory diseases. However, the prediction of the outcome is not simple, and other studies propose that trained immunity can induce a beneficial response both in AIF and autoimmune conditions by inducing anti-inflammatory responses. This article describes the metabolic and epigenetic mechanisms involved in trained immunity that affect Mo/Ma, contraposing the controversial evidence on how it may impact autoimmune/autoinflammation conditions.

Biased in favour.

Biased in favour.

MRI assessment of glutamine uptake correlates with the distribution of glutamine transporters and cancer stem cell markers

Glutamine provides carbon and nitrogen for macromolecular synthesis and participates in adenosine triphosphate (ATP) generation, anabolic metabolism, redox homeostasis, cell signaling, and cancer stem cell (CSC) metabolism. New treatment strategies targeting glutamine metabolism in cancer have emerged recently. We previously reported the magnetic resonance imaging (MRI) assessment of glutamine uptake by tumors and activated glutamine metabolism in CSC. In the present study, using MRI, we determined the correlation between glutamine uptake and the distribution of glutamine transporters, namely ASCT2 and SLC38A2 (SNAT2), glutaminase (GLS), and CSC markers, such as CD44 and CD166, in a mouse xenograft model of HT29 human colorectal cancer cells. MRI data revealed an obvious change in intensity following glutamine administration. Immunohistochemistry (IHC) results indicated that ASCT2 staining was stronger in regions that exhibited high glutamine uptake (p = 0.0079). Significant differences were found in the IHC staining intensities of SNAT2, GLS, and CSC markers in the areas of high and low glutamine uptake (p = 0.0079, p = 0.0159 and p = 0.0079, respectively). We also investigated the effect of an ASCT2 inhibitor on the uptake of glutamine using MRI. A statistically significant difference in the initial glutamine uptake was found after ASCT2 inhibitor administration. To conclude, glutamine uptake is positively correlated with the distribution of ASCT2 and certain CSC markers.

The MicroRNA miR-277 Controls Physiology and Pathology of the Adult Drosophila Midgut by Regulating the Expression of Fatty Acid β-Oxidation-Related Genes in Intestinal Stem Cells.

Cell division, growth, and differentiation are energetically costly and dependent processes. In adult stem cell-based epithelia, cellular identity seems to be coupled with a cell’s metabolic profile and vice versa. It is thus tempting to speculate that resident stem cells have a distinct metabolism, different from more committed progenitors and differentiated cells. Although investigated for many stem cell types in vitro, in vivo data of niche-residing stem cell metabolism is scarce. In adult epithelial tissues, stem cells, progenitor cells, and their progeny have very distinct functions and characteristics. In our study, we hypothesized and tested whether stem and progenitor cell types might have a distinctive metabolic profile in the intestinal lineage. Here, taking advantage of the genetically accessible adult Drosophila melanogaster intestine and the availability of ex vivo single cell sequencing data, we tested that hypothesis and investigated the metabolism of the intestinal lineage from stem cell (ISC) to differentiated epithelial cell in their native context under homeostatic conditions. Our initial in silico analysis of single cell RNAseq data and functional experiments identify the microRNA miR-277 as a posttranscriptional regulator of fatty acid β-oxidation (FAO) in the intestinal lineage. Low levels of miR-277 are detected in ISC and progressively rising miR-277 levels are found in progenitors during their growth and differentiation. Supporting this, miR-277-regulated fatty acid β-oxidation enzymes progressively declined from ISC towards more differentiated cells in our pseudotime single-cell RNAseq analysis and in functional assays on RNA and protein level. In addition, in silico clustering of single-cell RNAseq data based on metabolic genes validates that stem cells and progenitors belong to two independent clusters with well-defined metabolic characteristics. Furthermore, studying FAO genes in silico indicates that two populations of ISC exist that can be categorized in mitotically active and quiescent ISC, of which the latter relies on FAO genes. In line with an FAO dependency of ISC, forced expression of miR-277 phenocopies RNAi knockdown of FAO genes by reducing ISC size and subsequently resulting in stem cell death. We also investigated miR-277 effects on ISC in a benign and our newly developed CRISPR-Cas9-based colorectal cancer model and found effects on ISC survival, which as a consequence affects tumor growth, further underlining the importance of FAO in a pathological context. Taken together, our study provides new insights into the basal metabolic requirements of intestinal stem cell on β-oxidation of fatty acids evolutionarily implemented by a sole microRNA. Gaining knowledge about the metabolic differences and dependencies affecting the survival of two central and cancer-relevant cell populations in the fly and human intestine might reveal starting points for targeted combinatorial therapy in the hope for better treatment of colorectal cancer in the future.

Differential Oxygen Exposure Modulates Mesenchymal Stem Cell Metabolism and Proliferation through mTOR Signaling.

Mesenchymal stem cells reside under precise hypoxic conditions that are paramount in determining cell fate and behavior (metabolism, proliferation, differentiation, etc.). In this work, we show that different oxygen tensions promote a distinct proliferative response and affect the biosynthetic demand and global metabolic profile of umbilical cord-mesenchymal stem cells (UC-MSCs). Using both gas-based strategies and CoCl2 as a substitute for the costly hypoxic chambers, we found that specific oxygen tensions influence the fate of UC-MSCs differently. While 5% O2 potentiates proliferation, stimulates biosynthetic pathways, and promotes a global hypermetabolic profile, exposure to <1% O2 contributes to a quiescent-like cell state that relies heavily on anaerobic glycolysis. We show that using CoCl2 as a hypoxia substitute of moderate hypoxia has distinct metabolic effects, when compared with gas-based strategies. The present study also highlights that, while severe hypoxia regulates global translation via mTORC1 modulation, its effects on survival-related mechanisms are mainly modulated through mTORC2. Therefore, the experimental conditions used in this study establish a robust and reliable hypoxia model for UC-MSCs, providing relevant insights into how stem cells are influenced by their physiological environment, and how different strategies of modulating hypoxia may influence experimental outcomes.

Re-defining and tackling the emerging challenges in stem cell research and translation: A report of the 10th CSSCR annual meeting.

The 10th congress of the Chinese Society for Stem Cell Research was held from 11 to 13 October 2020 at Guiyang International Eco‐Conference Center in Guizhou (Southwest China) with 700 offline participants (and 500 online participants). With a theme adopted from a poem by Mao Zedong during the long march, ‘However difficult it might appear; the challenges will be overcome’, the congress provided opportunities for the fast‐growing field to exchange ideas among people from academia, industry and regulatory authorities, to help accelerate translation. Eight plenary lectures and six concurrent sessions on cell fate decision, stem cell metabolism, neural stem cells and neural regeneration, organoids and disease models, tissue and organ regeneration and clinical translation of stem cell research were covered, including 77 oral presentations and 75 poster presentations. The congress also included special programmes of a youth forum, a lecture award programme, a flagship journal forum and a dedicated networking session. This 3‐day event will significantly boost the stem cell research in an era closing to application.

Glucose Metabolism and Aging of Hematopoietic Stem and Progenitor Cells.

Comprehensive proteomics studies of human hematopoietic stem and progenitor cells (HSPC) have revealed that aging of the HSPC compartment is characterized by elevated glycolysis. This is in addition to deregulations found in murine transcriptomics studies, such as an increased differentiation bias towards the myeloid lineage, alterations in DNA repair, and a decrease in lymphoid development. The increase in glycolytic enzyme activity is caused by the expansion of a more glycolytic HSPC subset. We therefore developed a method to isolate HSPC into three distinct categories according to their glucose uptake (GU) levels, namely the GUhigh, GUinter and GUlow subsets. Single-cell transcriptomics studies showed that the GUhigh subset is highly enriched for HSPC with a differentiation bias towards myeloid lineages. Gene set enrichment analysis (GSEA) demonstrated that the gene sets for cell cycle arrest, senescence-associated secretory phenotype, and the anti-apoptosis and P53 pathways are significantly upregulated in the GUhigh population. With this series of studies, we have produced a comprehensive proteomics and single-cell transcriptomics atlas of molecular changes in human HSPC upon aging. Although many of the molecular deregulations are similar to those found in mice, there are significant differences. The most unique finding is the association of elevated central carbon metabolism with senescence. Due to the lack of specific markers, the isolation and collection of senescent cells have yet to be developed, especially for human HSPC. The GUhigh subset from the human HSPC compartment possesses all the transcriptome characteristics of senescence. This property may be exploited to accurately enrich, visualize, and trace senescence development in human bone marrow.

Metabolic regulation of somatic stem cells in vivo.

Metabolism has been studied mainly in cultured cells or at the level of whole tissues or whole organisms in vivo. Consequently, our understanding of metabolic heterogeneity among cells within tissues is limited, particularly when it comes to rare cells with biologically distinct properties, such as stem cells. Stem cell function, tissue regeneration and cancer suppression are all metabolically regulated, although it is not yet clear whether there are metabolic mechanisms unique to stem cells that regulate their activity and function. Recent work has, however, provided evidence that stem cells do have a metabolic signature that is distinct from that of restricted progenitors and that metabolic changes influence tissue homeostasis and regeneration. Stem cell maintenance throughout life in many tissues depends upon minimizing anabolic pathway activation and cell division. Consequently, stem cell activation by tissue injury is associated with changes in mitochondrial function, lysosome activity and lipid metabolism, potentially at the cost of eroding self-renewal potential. Stem cell metabolism is also regulated by the environment: stem cells metabolically interact with other cells in their niches and are able to sense and adapt to dietary changes. The accelerating understanding of stem cell metabolism is revealing new aspects of tissue homeostasis with the potential to promote tissue regeneration and cancer suppression.