Stem Cell Metabolism Research Articles

A CD10-OGP Membrane Peptolytic Signaling Axis in Fibroblasts Regulates Lipid Metabolism of Cancer Stem Cells via SCD1.

Carcinoma‐associated fibroblasts (CAFs) consist of heterogeneous subpopulations that play a critical role in the dynamics of the tumor microenvironment. The extracellular signals of CAFs have been attributed to the extracellular matrix, cytokines, cell surface checkpoints, and exosomes. In the present study, it is demonstrated that the CD10 transmembrane hydrolase expressed on a subset of CAFs supports tumor stemness and induces chemoresistance. Mechanistically, CD10 degenerates an antitumoral peptide termed osteogenic growth peptide (OGP). OGP restrains the expression of rate‐limiting desaturase SCD1 and inhibits lipid desaturation, which is required for cancer stem cells (CSCs). Targeting CD10 significantly improves the efficacy of chemotherapy in vivo. Clinically, CD10‐OGP signals are associated with the response to neoadjuvant chemotherapy in patients with breast cancer. The collective data suggest that a nexus between the niche and lipid metabolism in CSCs is a promising therapeutic target for breast cancer.

Report From the 6th International Meeting on Bone Marrow Adiposity (BMA2020).

The 6th International Meeting on Bone Marrow Adiposity (BMA) entitled “Marrow Adiposity: Bone, Aging, and Beyond” (BMA2020) was held virtually on September 9th and 10th, 2020. The mission of this meeting was to facilitate communication and collaboration among scientists from around the world who are interested in different aspects of bone marrow adiposity in health and disease. The BMA2020 meeting brought together 198 attendees from diverse research and clinical backgrounds spanning fields including bone biology, endocrinology, stem cell biology, metabolism, oncology, aging, and hematopoiesis. The congress featured an invited keynote address by Ormond MacDougald and ten invited speakers, in addition to 20 short talks, 35 posters, and several training and networking sessions. This report summarizes and highlights the scientific content of the meeting and the progress of the working groups of the BMA society (http://bma-society.org/).

Role of Lysophospholipid Metabolism in Chronic Myelogenous Leukemia Stem Cells.

Simple SummaryIn this review, I discuss our recent finding that lysophospholipid metabolism is essential for the maintenance of chronic myelogenous leukemia (CML) stem cells. Lysophospholipids have only one fatty acid chain and so are more hydrophilic than phospholipids, allowing them to act as lipid second messengers. We demonstrated that the stem cell quiescence and TKI resistance displayed by CML stem cells in vivo are sustained by the Gdpd3 enzyme involved in lysophospholipid metabolism. At the mechanistic level, Gdpd3 function allows lysophospholipid metabolism to suppress the AKT/mTORC1-mediated cell growth pathway while activating the stemness factors FOXO and β-catenin. Our results thus link lysophospholipid metabolism to CML stemness, and may thereby open up new therapeutic avenues to overcome CML relapse post-TKI therapy.It is well known that mature chronic myelogenous leukemia (CML) cells proliferate in response to oncogenic BCR–ABL1-dependent signaling, but how CML stem cells are able to survive in an oncogene-independent manner and cause disease relapse has long been elusive. Here, I put into the context of the broader literature our recent finding that lysophospholipid metabolism is essential for the maintenance of CML stem cells. I describe the fundamentals of lysophospholipid metabolism and discuss how one of its key enzymes, Glycerophosphodiester Phosphodiesterase Domain Containing 3 (Gdpd3), is responsible for maintaining the unique characteristics of CML stem cells. I also explore how this knowledge may be exploited to devise novel therapies for CML patients.

Maternal metabolic health drives mesenchymal stem cell metabolism and infant fat mass at birth.

Exposure to maternal obesity may promote metabolic dysfunction in offspring. We used infant mesenchymal stem cells (MSCs) to experimentally examine cellular mechanisms of intergenerational health transmission. Our earlier reports show MSCs collected from infants of mothers with obesity had a dichotomous distribution in metabolic efficiency; they were either efficient (Ef-Ob) or inefficient (In-Ob) with respect to fatty acid oxidation (FAO). Here, we sought to determine if this was due to a primary defect in FAO. Accordingly, we measured FAO in myogenic differentiating MSCs under 3 conditions: (a) myogenesis alone, (b) excess fatty acid exposure, and (c) excess fatty acid exposure plus a chemical uncoupler to increase metabolic rate. Compared with normal weight and Ef-Ob MSCs, In-Ob displayed lower FAO in myogenesis alone and after fatty acid plus uncoupler, indicating In-Ob were less metabolically flexible after increasing lipid availability and metabolic rate, demonstrating a primary deficit in FAO. MSC FAO was negatively associated with fasting maternal glucose and insulin and positively associated with fasting HDL-cholesterol. MSC FAO was negatively associated with infant fat mass. These data indicate a less favorable maternal metabolic milieu, independent of maternal BMI, reduces intrinsic MSC FAO and is linked to higher infant adiposity as early as birth.

SIRT1 regulates sphingolipid metabolism and neural differentiation of mouse embryonic stem cells through c-Myc-SMPDL3B.

Sphingolipids are important structural components of cell membranes and prominent signaling molecules controlling cell growth, differentiation, and apoptosis. Sphingolipids are particularly abundant in the brain, and defects in sphingolipid degradation are associated with several human neurodegenerative diseases. However, molecular mechanisms governing sphingolipid metabolism remain unclear. Here, we report that sphingolipid degradation is under transcriptional control of SIRT1, a highly conserved mammalian NAD+-dependent protein deacetylase, in mouse embryonic stem cells (mESCs). Deletion of SIRT1 results in accumulation of sphingomyelin in mESCs, primarily due to reduction of SMPDL3B, a GPI-anchored plasma membrane bound sphingomyelin phosphodiesterase. Mechanistically, SIRT1 regulates transcription of Smpdl3b through c-Myc. Functionally, SIRT1 deficiency-induced accumulation of sphingomyelin increases membrane fluidity and impairs neural differentiation in vitro and in vivo. Our findings discover a key regulatory mechanism for sphingolipid homeostasis and neural differentiation, further imply that pharmacological manipulation of SIRT1-mediated sphingomyelin degradation might be beneficial for treatment of human neurological diseases.

Lactate Reprograms Energy and Lipid Metabolism in Glucose-Deprived Oxidative Glioma Stem Cells.

Fast-growing tumors satisfy their bioenergetic needs by supplementing glucose with alternative carbon sources. Cancer stem cells are the most versatile and robust cells within malignant tumors. They avoid potentially lethal metabolic and other types of stress through flexible reprogramming of relevant pathways, but it has remained unclear whether alternative carbon sources are important for the maintenance of their tumor-propagating ability. Here we assessed the ability of glycolytic and oxidative murine glioma stem cells (GSCs) to grow in an ultralow glucose medium. Sphere formation assays revealed that exogenous lactate and acetate reversed the growth impairment of oxidative GSCs in such medium. Extracellular flux analysis showed that lactate supported oxygen consumption in these cells, whereas metabolomics analysis revealed that it increased the intracellular levels of tricarboxylic acid cycle intermediates, ATP, and GTP as well as increased adenylate and guanylate charge. Lactate also reversed the depletion of choline apparent in the glucose-deprived cells as well as reprogrammed phospholipid and fatty acid biosynthesis. This metabolic reprogramming was associated with a more aggressive phenotype of intracranial tumors formed by lactate-treated GSCs. Our results thus suggest that lactate is an important alternative energetic and biosynthetic substrate for oxidative GSCs, and that it sustains their growth under conditions of glucose deprivation.

LRRC17 regulates the bone metabolism of human bone marrow mesenchymal stem cells from patients with idiopathic necrosis of femoral head through Wnt signaling pathways: A preliminary report.

Idiopathic necrosis of the femoral head (INFH) is a common disease with unknown cause. Its successful treatment relies on the repair of the necrotic bone. The application of autologous mesenchymal stem cells (MSCs) has shown great promise in saving the patients from undergoing total hip arthroplasty. Leucine-rich repeat-containing 17 (LRRC17) is less expressed in patients with femoral head necrosis and LRRC17 can inhibit bone degradation. However, it remains unknown whether LRRC17 plays a role in the pathogenesis of INFH. The present study aimed to investigate the potential role and mechanism of LRRC17 in the pathogenesis and treatment of INFH. It was found that despite the similar cell morphology and MSC surface marker expressions of human bone marrow MSCs (BMSCs) isolated from patients with INFH (INFH-hBMSC) and femoral neck fracture (FNF) (FNF-hBMSC), INFH-hBMSC had higher percentage of apoptosis (P<0.05), as well as lower osteogenic potential and higher adipogenic potential (both P<0.05). However, there was no difference in cell proliferation between FNF-hBMSC and INFH-hBMSC (P>0.05). It was also confirmed that the expression of LRRC17 was lower in the bone tissue and hBMSCs from patients with INFH compared with patients with FNF (P<0.05). Overexpression of LRRC17 promoted osteogenesis and inhibited the adipogenesis in hBMSCs, accompanied with the increase of Wnt3a and β-catenin expressions, and the decrease of Wnt5a and receptor activator of nuclear factor κ-B ligand (Rankl) expressions (all, P<0.05). Furthermore, knockout of LRRC17 in hBMSCs inhibited the expression levels of osteogenic and promoted adipogenic markers, while decreasing Wnt3a and β-catenin expressions, and increasing Wnt5a and Rankl expressions (all, P<0.05). The present preliminary study suggested that imbalanced bone metabolism may be involved in the pathogenesis of INFH. The modulation of the LRRC17 gene may delay or even restore the balance of osteogenic and adipogenic differentiation in autologous BMSCs derived from patients with INFH, providing a new target for the treatment of INFH.

Nano-realgar suppresses lung cancer stem cell growth by repressing metabolic reprogramming.

Recent studies in cancer biology suggest that metabolic glucose reprogramming is a potential target for cancer treatment. However, little is known about drug intervention in the glucose metabolism of cancer stem cells (CSCs) and its related underlying mechanisms. The crude realgar powder was Nano-grinded to meets the requirements of Nano-pharmaceutical preparations, and Nano-realgar solution (NRS) was prepared for subsequent experiments. Isolation and characterization of lung cancer stem cells (LCSCs) was performed by magnetic cell sorting (MACS) and immunocytochemistry, respectively. Cell viability and intracellular glucose concentration were detected by MTT assay and glucose oxidase (GOD) kit. Protein expressions related to metabolic reprogramming was detected by ELISA assay. Determination of the expression of HIF-1α and PI3K/Akt/mTOR pathways was carried out by RT-PCR and western blotting analysis. A subcutaneous tumor model in BALB/c-nu mice was successfully established to evaluate the effects of Nano-realgar on tumor growth and histological structure, and the expression of HIF-1α in tumor tissues was measured by immunofluorescence. Nano-realgar inhibits cell viability and induces glucose metabolism in LCSCs, and inhibits protein expression related to metabolic reprogramming in a time- and dose-dependent manner. Nano-realgar downregulated the expression of HIF-1α and PI3K/Akt/mTOR pathways in vitro and in vivo. Nano-realgar inhibits tumor growth and changes the histological structure of tumors through in vivo experiments and consequently inhibits the constitutive activation of HIF-1α signaling. These results reveal that Nano-realgar inhibits tumor growth in vitro and in vivo by repressing metabolic reprogramming. This inhibitory effect potentially related to the downregulation HIF-1α expression via PI3K/Akt/mTOR pathway.

Selective Targeting of Unique Metabolic Properties of Leukemic Stem Cells in Acute Myeloid Leukemia

Current therapeutic options in the treatment of acute myeloid leukemia often succumb to high instances of relapse and subsequent mortality. Chemotherapy and radiotherapy have long been used as the standard treatment for this disease, remaining stagnant over the past few decades. Recently, a small self-renewing population of leukemic stem cells have been identified as drivers of cancer relapse and progression due to their increased resistance to anticancer therapeutics. This enables these cells to maintain a minimal residual disease and results in downstream differentiation, leading to relapse. Targeting these cells may lead to effective therapies that reduce relapse and mortality. Recently, the metabolic properties of leukemic stem cells have begun to be elucidated. Here, we discuss recent discoveries regarding the metabolism of leukemic stem cells and approaches to targeting their unique metabolic properties.

Role of colony-forming tissue stem cells in the macula flava of the human vocal fold in vivo.

ObjectivesOur previous investigations showed that tissue stem cells in the maculae flavae (a stem cell niche) form colonies in vivo like stem cells in vitro. However, the roles of colony‐forming cells in the maculae flavae in vivo have not yet been determined.This study investigated the metabolism of the colony‐forming tissue stem cells in the maculae flavae of the human adult vocal fold.Study designHistologic analysis of the human vocal folds.MethodsThree normal human adult vocal folds were investigated under transmission electron microscopy and light microscopy including immunohistochemistry.ResultsMitochondrial cristae of the colony‐forming cells in the maculae flavae were sparse. Hence, the microstructural features of the mitochondria suggested that their metabolic activity and oxidative phosphorylation were low. Colony‐forming cells strongly expressed glucose transporter‐1 and glycolytic enzymes (hexokinase II, glyceraldehyde‐3‐phosphate dehydrogenase and lactate dehydrogenase A). The colony‐forming cells did not express phosphofructokinase‐1 but did express glucose‐6‐phosphate dehydrogenase indicating the cells relied more on the pentose phosphate pathway. Since the colony‐forming cells expressed lactate dehydrogenase A, cells seemed to rely more on anaerobic glycolysis in an anaerobic microenvironment.ConclusionsThe present study is consistent with the hypothesis that the colony‐forming tissue stem cells in the maculae flavae of the human adult vocal fold seemed to rely more on anaerobic glycolysis using the pentose phosphate pathway for energy supply in vivo. Microstructural features of the mitochondria and expressed glycolytic enzymes of the colony‐forming cells in the maculae flavae suggested that the oxidative phosphorylation activity was low.In an anaerobic microenvironment in vivo, there is likely a complex cross‐talk regarding the metabolism between the colony‐forming aggregated cells along the adhesion machinery and chemical signaling pathways, which reduces toxic oxygen species and is favorable to maintaining the stemness and undifferentiated states of the tissue stem cells.Level of EvidenceNA.

Role of Aberrant Lipid Metabolism of Cancer Stem Cells in Cancer Progression.

Cancer stem cells (CSCs) represent a small population of cancer cells that are able to self-renew and initiate tumors, which undergo epigenetic, epithelial-mesenchymal, immunological, and metabolic reprogramming to adapt to the tumor microenvironment as well as survive host defense or therapeutic insults. The metabolic reprogramming that accompanies cancer onset is known to be critical for the disease pathogenesis. A coordinated dysregulation of lipid metabolism is observed in nearly all cancer types. In addition to fulfilling the basic requirements of structural lipids for membrane synthesis, lipids function importantly as signaling molecules and contribute to energy homeostasis. In this review, we summarize the current progress in the attractive research field of aberrant lipid metabolism regarding CSCs in cancer progression, which provides insights into therapeutic agents targeting CSCs based upon their modulation of lipid metabolism.

Biotin Controls Intestinal Stem Cell Mitosis and Host-Microbiome Interactions

Detrimental alterations in intestinal microbiota, known as dysbiosis, predispose to inflammation that can lead to tumorigenesis. We show that dysbiosis can also result from impaired intestinal stem cell (ISC) metabolism. We found that the Drosophila intestinal ISC-specific biotin transporter Smvt is necessary for Jak/Stat pathway-mediated ISC mitosis. ISC-specific Smvt silencing impairs intestinal maintenance, which can be partially-rescued by the human Smvt, encoded by SLC5A6. Smvt-deficient flies exhibit microbial dysbiosis, whereby the growth of Providencia sneebia, an opportunistic pathogen, is favored. Dysbiosis correlates with increased Nox expression, ROS and enterocyte apoptosis. Flies acquire biotin from their diet and microbiota. We found that when dietary biotin is scarce, biotin-producing commensals, e.g. E. coli, can rescue reduced ISC mitosis. Smvt and commensals also control intestinal tumor growth. Our findings suggest that direct modification of the gut microbiome by biotin can serve as an approach for the treatment of dysbiosis-promoted diseases and tumorigenesis control.

Natural killer cells efficiently target multiple myeloma clonogenic tumor cells

The multiple myeloma (MM) landscape has changed in the last few years, but most patients eventually relapse because current treatment modalities do not target clonogenic stem cells, which are drug-resistant and can self-renew. We hypothesized that side population (SP) cells represent myeloma clonogenic stem cells and, searching for new treatment strategies, analyzed the anti-myeloma activity of natural killer (NK) cells against clonogenic cells. Activated and expanded NK cells (NKAE) products were obtained by co-culturing NK cells from MM patients with K562-mb15-41BBL cell line and characterized by flow cytometry. Functional experiments against MM cells were performed by Eu-TDA release assays and methylcellulose clonogenic assays. Side population was detected by Dye Cycle Violet labeling and then characterized by flow cytometry and RNA-Seq. Self-renewal capacity was tested by clonogenic assays. Sorting of both kind of cells was performed for time-lapse microscopy experiments. SP cells exhibited self-renewal potential and overexpressed genes involved in stem cell metabolism. NK cells from MM patients exhibited dysregulation and had lower anti-tumor potential against clonogenic cells than healthy donors’ NK cells. Patients’ NK cells were activated and expanded. These cells recovered cytotoxic activity and could specifically destroy clonogenic myeloma cells. They also had a highly cytotoxic phenotype expressing NKG2D receptor. Blocking NKG2D receptor decreased NK cell activity against clonogenic myeloma cells, and activated NK cells were able to destroy SP cells, which expressed NKG2D ligands. SP cells could represent the stem cell compartment in MM. This is the first report describing NK cell activity against myeloma clonogenic cells.

Challenges in Studying Stem Cell Metabolism.

The expanding field of stem cell metabolism has been supported by technical advances in metabolite profiling and novel functional analyses. While use of these methodologies has been fruitful, many challenges are posed by the intricacies of culturing stem cells invitro, along with the distinctive scarcity of adult tissue stem cells and the complexities of their niches invivo. This review provides an examination of the methodologies used to characterize stem cell metabolism, highlighting their utility while placing a sharper focus on their limitations and hurdles the field needs to overcome for the optimal study of stem cell metabolic networks.

Lysosomal Regulation of Metabolism in Quiescent Hematopoietic Stem Cells: More than Just Autophagy

The depth of quiescence in hematopoietic stem cells (HSCs) dictates their potency and is sensitive to metabolic perturbations. Recent evidence suggests that lysosomal functions distinct from autophagic processes are pivotal in regulating quiescence versus activation by potential control of the access to a nutrient reservoir required for HSC activation.

Targeting Energy Metabolism in Cancer Stem Cells: Progress and Challenges in Leukemia and Solid Tumors.

Malignant stem cells have long been considered a key therapeutic target in leukemia. Therapeutic strategies designed to target the fundamental biology of leukemia stem cells while sparing normal hematopoietic cells may provide better outcomes for leukemia patients. One process in leukemia stem cell biology that has intriguing therapeutic potential is energy metabolism. In this article we discuss the metabolic properties of leukemia stem cells and how targeting energy metabolism may provide more effective therapeutic regimens for leukemia patients. In addition, we highlight the similarities and differences in energy metabolism between leukemia stem cells and malignant stem cells from solid tumors.

A perspective analysis: microRNAs, glucose metabolism, and drug resistance in colon cancer stem cells.

A perspective analysis: microRNAs, glucose metabolism, and drug resistance in colon cancer stem cells.

Mitochondrial Dynamics in the Drosophila Ovary Regulates Germ Stem Cell Number, Cell Fate, and Female Fertility.

The fate and proliferative capacity of stem cells have been shown to strongly depend on their metabolic state. Mitochondria are the powerhouses of the cell being responsible for energy production via oxidative phosphorylation (OxPhos) as well as for several other metabolic pathways. Mitochondrial activity strongly depends on their structural organization, with their size and shape being regulated by mitochondrial fusion and fission, a process known as mitochondrial dynamics. However, the significance of mitochondrial dynamics in the regulation of stem cell metabolism and fate remains elusive. Here, we characterize the role of mitochondria morphology in female germ stem cells (GSCs) and in their more differentiated lineage. Mitochondria are particularly important in the female GSC lineage. Not only do they provide these cells with their energy requirements to generate the oocyte but they are also the only mitochondria pool to be inherited by the offspring. We show that the undifferentiated GSCs predominantly have fissed mitochondria, whereas more differentiated germ cells have more fused mitochondria. By reducing the levels of mitochondrial dynamics regulators, we show that both fused and fissed mitochondria are required for the maintenance of a stable GSC pool. Surprisingly, we found that disrupting mitochondrial dynamics in the germline also strongly affects nurse cells morphology, impairing egg chamber development and female fertility. Interestingly, reducing the levels of key enzymes in the Tricarboxylic Acid Cycle (TCA), known to cause OxPhos reduction, also affects GSC number. This defect in GSC self-renewal capacity indicates that at least basal levels of TCA/OxPhos are required in GSCs. Our findings show that mitochondrial dynamics is essential for female GSC maintenance and female fertility, and that mitochondria fusion and fission events are dynamically regulated during GSC differentiation, possibly to modulate their metabolic profile.

Glycolytic activity of the tissue stem cells in the macula flava of the human vocal fold.

ObjectivesIn our previous studies, the features of the mitochondria of tissue stem cells in the maculae flavae of the human vocal fold suggested that their metabolic activity and oxidative phosphorylation was low. This study investigated the metabolic activity, especially glycolysis of the tissue stem cells in the maculae flavae of the human adult vocal fold.Study DesignHistologic analysis of the human vocal folds.MethodsThree normal human adult vocal folds obtained from autopsy cases were investigated using immunohistochemistry.ResultsAmong the three phenotypes of cells in the human adult maculae flavae, the vocal fold stellate cell‐like cells strongly expressed glucose transporter‐1. Three phenotypes of cells in the human adult maculae flavae expressed glycolytic enzymes (hexokinase II, glyceraldehyde‐3‐phosphate dehydrogenase and lactate dehydrogenase A) indicating the tissue stem cells in the maculae flavae relied more on glycolysis. The cells did not express phosphofructokinase‐1 but did express glucose‐6‐phosphate dehydrogenase indicating the cells relied more on the pentose phosphate pathway. The cells expressed lactate dehydrogenase A indicating the maculae flavae of the human adult vocal fold was likely to be an anaerobic microenvironment.ConclusionsThe present study is consistent with the hypothesis that the tissue stem cells in the maculae flavae of the human vocal fold seem to rely more on anaerobic glycolysis, especially by the pentose phosphate pathway, for energy supply. The metabolism of the tissue stem cells in the maculae flavae of the human adult vocal fold is likely to prevent toxic reaction oxygen species and be favorable to maintaining the stemness and undifferentiated states of the tissue stem cells in the stem cells system.Level of EvidenceNA.

Mitochondrial Metabolism in the Intestinal Stem Cell Niche-Sensing and Signaling in Health and Disease.

Mitochondrial metabolism, dynamics, and stress responses in the intestinal stem cell niche play a pivotal role in regulating intestinal epithelial cell homeostasis, including self-renewal and differentiation. In addition, mitochondria are increasingly recognized for their involvement in sensing the metabolic environment and their capability of integrating host and microbial-derived signals. Gastrointestinal diseases such as inflammatory bowel diseases and colorectal cancer are characterized by alterations of intestinal stemness, the microbial milieu, and mitochondrial metabolism. Thus, mitochondrial function emerges at the interface of determining health and disease, and failure to adapt mitochondrial function to environmental cues potentially results in aberrant tissue responses. A mechanistic understanding of the underlying role of mitochondrial fitness in intestinal pathologies is still in its infancy, and therapies targeting mitochondrial (dys)function are currently lacking. This review discusses mitochondrial signaling and metabolism in intestinal stem cells and Paneth cells as critical junction translating host- and microbe-derived signals into epithelial responses. Consequently, we propose mitochondrial fitness as a hallmark for intestinal epithelial cell plasticity, determining the regenerative capacity of the epithelium.