scholarly journals Stem Cell Metabolism: Powering Cell-Based Therapeutics

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2490
Author(s):  
Vagner O. C. Rigaud ◽  
Robert Hoy ◽  
Sadia Mohsin ◽  
Mohsin Khan
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Environmental Changes ◽  
Cell Function ◽  
Cell Metabolism ◽  
Cardiac Repair ◽  
Critical Determinant ◽  
Environmental Signals ◽  
Cellular Processes ◽  
Stem Cell Metabolism

Cell-based therapeutics for cardiac repair have been extensively used during the last decade. Preclinical studies have demonstrated the effectiveness of adoptively transferred stem cells for enhancement of cardiac function. Nevertheless, several cell-based clinical trials have provided largely underwhelming outcomes. A major limitation is the lack of survival in the harsh cardiac milieu as only less than 1% donated cells survive. Recent efforts have focused on enhancing cell-based therapeutics and understanding the biology of stem cells and their response to environmental changes. Stem cell metabolism has recently emerged as a critical determinant of cellular processes and is uniquely adapted to support proliferation, stemness, and commitment. Metabolic signaling pathways are remarkably sensitive to different environmental signals with a profound effect on cell survival after adoptive transfer. Stem cells mainly generate energy through glycolysis while maintaining low oxidative phosphorylation (OxPhos), providing metabolites for biosynthesis of macromolecules. During commitment, there is a shift in cellular metabolism, which alters cell function. Reprogramming stem cell metabolism may represent an attractive strategy to enhance stem cell therapy for cardiac repair. This review summarizes the current literature on how metabolism drives stem cell function and how this knowledge can be applied to improve cell-based therapeutics for cardiac repair.

scholarly journals RNA m6A Modification Plays a Key Role in Maintaining Stem Cell Function in Normal and Malignant Hematopoiesis

2021 ◽  
Vol 9 ◽  
Author(s):  
Peipei Wang ◽  
Mengdie Feng ◽  
Guoqiang Han ◽  
Rong Yin ◽  
Yashu Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Myeloid Leukemia ◽  
Cell Function ◽  
Leukemia Stem Cells ◽  
Hematopoietic Stem ◽  
Cellular Processes ◽  
Acute Myeloid

N6-methyladenosine (m6A) is a commonly modification of mammalian mRNAs and plays key roles in various cellular processes. Emerging evidence reveals the importance of RNA m6A modification in maintaining stem cell function in normal hematopoiesis and leukemogenesis. In this review, we first briefly summarize the latest advances in RNA m6A biology, and further highlight the roles of m6A writers, readers and erasers in normal hematopoiesis and acute myeloid leukemia. Moreover, we also discuss the mechanisms of these m6A modifiers in preserving the function of hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs), as well as potential strategies for targeting m6A modification related pathways. Overall, we provide a comprehensive summary and our insights into the field of RNA m6A in normal hematopoiesis and leukemia pathogenesis.

Evidence for Restricted Glycolytic Metabolism in Primary CD133+ Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1726-1726 ◽  
Author(s):  
Ruediger Alt ◽  
Thomas Riemer ◽  
Oliver Fiehn ◽  
Dietger Niederwieser ◽  
Michael Cross
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Cell Metabolism ◽  
Flow Cytometric Analysis ◽  
Small Scale ◽  
Glycolytic Metabolism ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Stem Cell Metabolism

Abstract The slow cycling, location and hypoxia-resistance of hematopoietic stem cells are suggestive of a restricted metabolism. We propose that HSC metabolism is adapted to unique metabolic conditions supplied by the stem cell niche, and that a combination of the metabolic and signalling environments acts to support stem cell amplification and to limit it to a narrowly-defined and physiologically rare set of sites. To investigate this possibility, we have established moderate throughput, small scale cultures to examine the metabolic characteristics of primary CD133+ cells isolated from umbilical cord blood. A screen of carbon and energy sources revealed that pyruvate (but neither fatty acids nor amino acids) can replace glutamine as a major substrate. The fact that pyruvate contributes significantly to the cellular metabolism even in the presence of glucose suggests that CD133+ cells employ an unusually low level of glycolysis. Flow cytometric analysis of surface markers before and after culture confirmed that the addition of glucose (0mM, 5mM and 25mM) or insulin (0μg/mL, 4 μg/mL) increased the overall cell yield, but had no effect on the proliferation of early cells (CD133+, CD34+ and c-kit+). In parallel, metabolic profiling of undifferentiated and differentiated FDCPmix cells using gas chromatography and mass spectrometry techniques revealed an accumulation of glucose in the self-renewing (undifferentiated) population. Taken together, these observations suggest that glycolysis makes little contribution to stem cell metabolism, and that hematopoietic stem cells (as has been suggested for germ cells) may instead use glycolytic products supplied by stromal cells. Furthermore, our studies have revealed an unexpected effect of osmolarity on both glucose metabolism and self-renewal, in that an increase in osmolarity from 0,32 Osm/Kg to 0,36 Osm/kg reduced the rate of glucose-dependent proliferation of CD133+ cells without reducing the yield of early (CD133+ CD34+, ckit+) cells. Similarly, both the proportion of self-renewing cells in FDCPmix cultures and the recruitment of these cells to active self-renewal in semi-solid media in a colony forming assay were found to be increased at higher osmolarity. This suggests that high osmolarities suppreses both glycolytic metabolism and proliferation rate, but favour the maintenance of “early” progenitors. Finally, we have applied our assay to test a range of different growth factor combinations (of SCF, Flt3-ligand, TPO, IL3, IL6, IL7, IL11 and TGF-b) in 18% and 1% O2, and found that hypoxia extends markedly the range and magnitude of the proliferation response. Taken together, our results suggest that hematopoietic stem cells are indeed adapted to a rare metabolic microenvironment which includes (but is probably not limited to) low oxygen and glucose concentrations, and that the metabolic environment is likely to influence strongly the response to growth factors. A thorough understanding of stem cell metabolism may therefore provide a basis for more controlled manipulation of HSC in vitro.

Stem Cell Function, Self-Renewal, Heterogeneity, and Regenerative Potential in Skeletal Muscle Stem Cells

2012 ◽  
Vol 2 (1) ◽  
pp. 11-21
Author(s):  
Silvia Cristini ◽  
Giulio Alessandri ◽  
Francesco Acerbi ◽  
Daniela Tavian ◽  
Eugenio A. Parati ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Stem Cell ◽  
Cell Function ◽  
Self Renewal ◽  
Muscle Stem Cells ◽  
Skeletal Muscle Stem Cells

Stem Cell Function, Self-Renewal, Heterogeneity, and Regenerative Potential in Skeletal Muscle Stem Cells

2012 ◽  
Vol 2 (1) ◽  
pp. 11-21
Author(s):  
Silvia Cristini ◽  
Giulio Alessandri ◽  
Francesco Acerbi ◽  
Daniela Tavian ◽  
Eugenio A. Parati ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Stem Cell ◽  
Cell Function ◽  
Self Renewal ◽  
Muscle Stem Cells ◽  
Skeletal Muscle Stem Cells

scholarly journals Multiple Roles for Cholinergic Signaling from the Perspective of Stem Cell Function

2021 ◽  
Vol 22 (2) ◽  
pp. 666
Author(s):  
Toshio Takahashi
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Function ◽  
Cell Activity ◽  
Embryonic Stem ◽  
Cholinergic Neurons ◽  
Cell Types ◽  
Proliferative Potential ◽  
True Nature ◽  
Cholinergic Signaling

Stem cells have extensive proliferative potential and the ability to differentiate into one or more mature cell types. The mechanisms by which stem cells accomplish self-renewal provide fundamental insight into the origin and design of multicellular organisms. These pathways allow the repair of damage and extend organismal life beyond that of component cells, and they probably preceded the evolution of complex metazoans. Understanding the true nature of stem cells can only come from discovering how they are regulated. The concept that stem cells are controlled by particular microenvironments, also known as niches, has been widely accepted. Technical advances now allow characterization of the zones that maintain and control stem cell activity in several organs, including the brain, skin, and gut. Cholinergic neurons release acetylcholine (ACh) that mediates chemical transmission via ACh receptors such as nicotinic and muscarinic receptors. Although the cholinergic system is composed of organized nerve cells, the system is also involved in mammalian non-neuronal cells, including stem cells, embryonic stem cells, epithelial cells, and endothelial cells. Thus, cholinergic signaling plays a pivotal role in controlling their behaviors. Studies regarding this signal are beginning to unify our understanding of stem cell regulation at the cellular and molecular levels, and they are expected to advance efforts to control stem cells therapeutically. The present article reviews recent findings about cholinergic signaling that is essential to control stem cell function in a cholinergic niche.

scholarly journals Empowering Muscle Stem Cells for the Treatment of Duchenne Muscular Dystrophy

2021 ◽  
pp. 1-14
Author(s):  
Romina L. Filippelli ◽  
Natasha C. Chang
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Cell Function ◽  
Critical Role ◽  
Membrane Integrity ◽  
Muscle Membrane ◽  
Muscle Stem Cell ◽  
Muscle Stem Cells

Duchenne muscular dystrophy (DMD) is a devastating and debilitating muscle degenerative disease affecting 1 in every 3,500 male births worldwide. DMD is progressive and fatal; accumulated weakening of the muscle tissue leads to an inability to walk and eventual loss of life due to respiratory and cardiac failure. Importantly, there remains no effective cure for DMD. DMD is caused by defective expression of the <i>DMD</i> gene, which encodes for dystrophin, a component of the dystrophin glycoprotein complex. In muscle fibers, this protein complex plays a critical role in maintaining muscle membrane integrity. Emerging studies have shown that muscle stem cells, which are adult stem cells responsible for muscle repair, are also affected in DMD. DMD muscle stem cells do not function as healthy muscle stem cells, and their impairment contributes to disease progression. Deficiencies in muscle stem cell function include impaired establishment of cell polarity leading to defective asymmetric stem cell division, reduced myogenic commitment, impaired differentiation, altered metabolism, and enhanced entry into senescence. Altogether, these findings indicate that DMD muscle stem cells are dysfunctional and have impaired regenerative potential. Although recent advances in adeno-associated vector and antisense oligonucleotide-mediated mechanisms for gene therapy have shown clinical promise, the current therapeutic strategies for muscular dystrophy do not effectively target muscle stem cells and do not address the deficiencies in muscle stem cell function. Here, we discuss the merits of restoring endogenous muscle stem cell function in degenerating muscle as a viable regenerative medicine strategy to mitigate DMD.

scholarly journals Set1 Targets Genes with Essential Identity and Tumor-Suppressing Functions in Planarian Stem Cells

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1182
Author(s):  
Prince Verma ◽  
Court K. M. Waterbury ◽  
Elizabeth M. Duncan
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Mammalian Cells ◽  
Cell Function ◽  
Genotoxic Stress ◽  
Specific Gene ◽  
Cell Identity ◽  
Chromatin Signature ◽  
Lysine Methyltransferase

Tumor suppressor genes (TSGs) are essential for normal cellular function in multicellular organisms, but many TSGs and tumor-suppressing mechanisms remain unknown. Planarian flatworms exhibit particularly robust tumor suppression, yet the specific mechanisms underlying this trait remain unclear. Here, we analyze histone H3 lysine 4 trimethylation (H3K4me3) signal across the planarian genome to determine if the broad H3K4me3 chromatin signature that marks essential cell identity genes and TSGs in mammalian cells is conserved in this valuable model of in vivo stem cell function. We find that this signature is indeed conserved on the planarian genome and that the lysine methyltransferase Set1 is largely responsible for creating it at both cell identity and putative TSG loci. In addition, we show that depletion of set1 in planarians induces stem cell phenotypes that suggest loss of TSG function, including hyperproliferation and an abnormal DNA damage response (DDR). Importantly, this work establishes that Set1 targets specific gene loci in planarian stem cells and marks them with a conserved chromatin signature. Moreover, our data strongly suggest that Set1 activity at these genes has important functional consequences both during normal homeostasis and in response to genotoxic stress.

scholarly journals Cancer stem cell metabolism: target for cancer therapy

BMB Reports ◽  
2018 ◽  
Vol 51 (7) ◽  
pp. 319-326 ◽  
Author(s):  
Young Chan Chae ◽  
Jae Ho Kim
Keyword(s):  
Stem Cell ◽  
Cancer Therapy ◽  
Cancer Stem Cell ◽  
Cell Metabolism ◽  
Stem Cell Metabolism

scholarly journals Single Cell Phenotyping Reveals Heterogeneity among Haematopoietic Stem Cells Following Infection

2016 ◽  
Author(s):  
Adam L MacLean ◽  
Maia A Smith ◽  
Juliane Liepe ◽  
Aaron Sim ◽  
Reema Khorshed ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Single Cell ◽  
Life History Theory ◽  
Cell Function ◽  
Trichinella Spiralis ◽  
Haematopoietic Stem Cell ◽  
Haematopoietic Stem Cells ◽  
Hsc Niche

AbstractThe haematopoietic stem cell (HSC) niche provides essential micro-environmental cues for the production and maintenance of HSCs within the bone marrow. During inflammation, haematopoietic dynamics are perturbed, but it is not known whether changes to the HSC-niche interaction occur as a result. We visualise HSCs directly in vivo, enabling detailed analysis of the 3D niche dynamics and migration patterns in murine bone marrow following Trichinella spiralis infection. Spatial statistical analysis of these HSC trajectories reveals two distinct modes of HSC behaviour: (i) a pattern of revisiting previously explored space, and (ii) a pattern of exploring new space. Whereas HSCs from control donors predominantly follow pattern (i), those from infected mice adopt both strategies. Using detailed computational analyses of cell migration tracks and life-history theory, we show that the increased motility of HSCs following infection can, perhaps counterintuitively, enable mice to cope better in deteriorating HSC-niche micro-environments following infection.Author SummaryHaematopoietic stem cells reside in the bone marrow where they are crucially maintained by an incompletely-determined set of niche factors. Recently it has been shown that chronic infection profoundly affects haematopoiesis by exhausting stem cell function, but these changes have not yet been resolved at the single cell level. Here we show that the stem cell–niche interactions triggered by infection are heterogeneous whereby cells exhibit different behavioural patterns: for some, movement is highly restricted, while others explore much larger regions of space over time. Overall, cells from infected mice display higher levels of persistence. This can be thought of as a search strategy: during infection the signals passed between stem cells and the niche may be blocked or inhibited. Resultantly, stem cells must choose to either ‘cling on’, or to leave in search of a better environment. The heterogeneity that these cells display has immediate consequences for translational therapies involving bone marrow transplant, and the effects that infection might have on these procedures.

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