scispace - formally typeset
Search or ask a question
Journal ArticleDOI

Lactate dehydrogenase activity drives hair follicle stem cell activation

TL;DR: It is demonstrated that HFSCs utilize glycolytic metabolism and produce significantly more lactate than other cells in the epidermis, and small molecules that increase lactate production by stimulating Myc levels or inhibiting Mpc1 carrier activity and can topically induce the hair cycle are identified.
Abstract: Although normally dormant, hair follicle stem cells (HFSCs) quickly become activated to divide during a new hair cycle. The quiescence of HFSCs is known to be regulated by a number of intrinsic and extrinsic mechanisms. Here we provide several lines of evidence to demonstrate that HFSCs utilize glycolytic metabolism and produce significantly more lactate than other cells in the epidermis. Furthermore, lactate generation appears to be critical for the activation of HFSCs as deletion of lactate dehydrogenase (Ldha) prevented their activation. Conversely, genetically promoting lactate production in HFSCs through mitochondrial pyruvate carrier 1 (Mpc1) deletion accelerated their activation and the hair cycle. Finally, we identify small molecules that increase lactate production by stimulating Myc levels or inhibiting Mpc1 carrier activity and can topically induce the hair cycle. These data suggest that HFSCs maintain a metabolic state that allows them to remain dormant and yet quickly respond to appropriate proliferative stimuli.

Content maybe subject to copyright    Report

Citations
More filters
Journal ArticleDOI
TL;DR: The biochemical and genetic principles of how metabolism can influence chromatin biology and epigenetics are described, the functional roles of this interplay in developmental and cancer biology are discussed, and future directions in this rapidly emerging area are presented.
Abstract: The substrates used to modify nucleic acids and chromatin are affected by nutrient availability and the activity of metabolic pathways. Thus, cellular metabolism constitutes a fundamental component of chromatin status and thereby of genome regulation. Here we describe the biochemical and genetic principles of how metabolism can influence chromatin biology and epigenetics, discuss the functional roles of this interplay in developmental and cancer biology, and present future directions in this rapidly emerging area.

353 citations

Journal ArticleDOI
TL;DR: It is shown that a 24 hr fast augments intestinal stem cell (ISC) function in young and aged mice by inducing a fatty acid oxidation (FAO) program and that pharmacological activation of this program mimics many effects of fasting.

237 citations


Cites background from "Lactate dehydrogenase activity driv..."

  • ...Two recent studies demonstrated that limiting pyruvate oxidation enhances intestinal and hair follicle stem cells, raising the possibility that a switch to FAOmay underlie some of these effects (Flores et al., 2017; Schell et al., 2017)....

    [...]

Journal ArticleDOI
TL;DR: It is demonstrated that LAB-type symbiont-derived lactate plays a pivotal role in promoting ISC-mediated epithelial development in a Gpr81-dependent manner and protected mice in response to gut injury provoked by combined treatments with radiation and chemotherapy drug.

236 citations

Journal ArticleDOI
TL;DR: How mitochondria can serve as signalling organelles that modify the fate of stem cells in the brain is discussed, which has major implications in physiological and pathological conditions.
Abstract: Emerging evidence now indicates that mitochondria are central regulators of neural stem cell (NSC) fate decisions and are crucial for both neurodevelopment and adult neurogenesis, which in turn contribute to cognitive processes in the mature brain. Inherited mutations and accumulated damage to mitochondria over the course of ageing serve as key factors underlying cognitive defects in neurodevelopmental disorders and neurodegenerative diseases, respectively. In this Review, we explore the recent findings that implicate mitochondria as crucial regulators of NSC function and cognition. In this respect, mitochondria may serve as targets for stem-cell-based therapies and interventions for cognitive defects.

219 citations

Journal ArticleDOI
TL;DR: It is demonstrated that limiting mitochondrial pyruvate metabolism is necessary and sufficient to maintain the proliferation of intestinal stem cells and to understand the role this transition from glycolysis to pyruVate oxidation plays in stem cell maintenance and differentiation.
Abstract: Most differentiated cells convert glucose to pyruvate in the cytosol through glycolysis, followed by pyruvate oxidation in the mitochondria. These processes are linked by the mitochondrial pyruvate carrier (MPC), which is required for efficient mitochondrial pyruvate uptake. In contrast, proliferative cells, including many cancer and stem cells, perform glycolysis robustly but limit fractional mitochondrial pyruvate oxidation. We sought to understand the role this transition from glycolysis to pyruvate oxidation plays in stem cell maintenance and differentiation. Loss of the MPC in Lgr5-EGFP-positive stem cells, or treatment of intestinal organoids with an MPC inhibitor, increases proliferation and expands the stem cell compartment. Similarly, genetic deletion of the MPC in Drosophila intestinal stem cells also increases proliferation, whereas MPC overexpression suppresses stem cell proliferation. These data demonstrate that limiting mitochondrial pyruvate metabolism is necessary and sufficient to maintain the proliferation of intestinal stem cells.

217 citations

References
More filters
Journal ArticleDOI
16 Jan 2004-Science
TL;DR: It is found that these cells rarely divide within their niche but change properties abruptly when stimulated to exit, and their transcriptional profile is determined, which, when compared to progeny and other SCs, defines the niche.
Abstract: Many adult regenerative cells divide infrequently but have high proliferative capacity. We developed a strategy to fluorescently label slow-cycling cells in a cell type-specific fashion. We used this method to purify the label-retaining cells (LRCs) that mark the skin stem cell (SC) niche. We found that these cells rarely divide within their niche but change properties abruptly when stimulated to exit. We determined their transcriptional profile, which, when compared to progeny and other SCs, defines the niche. Many of the >100 messenger RNAs preferentially expressed in the niche encode surface receptors and secreted proteins, enabling LRCs to signal and respond to their environment.

1,956 citations

Journal ArticleDOI
03 Sep 2004-Cell
TL;DR: It is suggested that the niche microenvironment imposes intrinsic "stemness" features without restricting the establishment of epithelial polarity and changes in gene expression.

1,369 citations

Journal ArticleDOI
TL;DR: It is shown that bulge cells in adult mice generate all epithelial cell types within the intact follicle and hair during normal hair follicle cycling and provide potential targets for the treatment of hair loss and other disorders of skin and hair.
Abstract: The hair follicle bulge possesses putative epithelial stem cells. Characterization of these cells has been hampered by the inability to target bulge cells genetically. Here, we use a Keratin1-15 (Krt1-15, also known as K15) promoter to target mouse bulge cells with an inducible Cre recombinase construct or with the gene encoding enhanced green fluorescent protein (EGFP), which allow for lineage analysis and for isolation of the cells. We show that bulge cells in adult mice generate all epithelial cell types within the intact follicle and hair during normal hair follicle cycling. After isolation, adult Krt1-15-EGFP-positive cells reconstituted all components of the cutaneous epithelium and had a higher proliferative potential than Krt1-15-EGFP-negative cells. Genetic profiling of hair follicle stem cells revealed several known and unknown receptors and signaling pathways important for maintaining the stem cell phenotype. Ultimately, these findings provide potential targets for the treatment of hair loss and other disorders of skin and hair.

1,245 citations

Journal ArticleDOI
TL;DR: It is shown that ablation of bulge cells by targeting them with a suicide gene encoding herpes simplex virus thymidine kinase leads to complete loss of hair follicles but survival of the epidermis, indicating that bulge stem cells respond rapidly to epidermal wounding by generating short-lived 'transient amplifying' cells responsible for acute wound repair.
Abstract: The discovery of long-lived epithelial stem cells in the bulge region of the hair follicle led to the hypothesis that epidermal renewal and epidermal repair after wounding both depend on these cells. To determine whether bulge cells are necessary for epidermal renewal, here we have ablated these cells by targeting them with a suicide gene encoding herpes simplex virus thymidine kinase (HSV-TK) using a Keratin 1-15 (Krt1-15) promoter. We show that ablation leads to complete loss of hair follicles but survival of the epidermis. Through fate-mapping experiments, we find that stem cells in the hair follicle bulge do not normally contribute cells to the epidermis which is organized into epidermal proliferative units, as previously predicted. After epidermal injury, however, cells from the bulge are recruited into the epidermis and migrate in a linear manner toward the center of the wound, ultimately forming a marked radial pattern. Notably, although the bulge-derived cells acquire an epidermal phenotype, most are eliminated from the epidermis over several weeks, indicating that bulge stem cells respond rapidly to epidermal wounding by generating short-lived 'transient amplifying' cells responsible for acute wound repair. Our findings have implications for both gene therapy and developing treatments for wounds because it will be necessary to consider epidermal and hair follicle stem cells as distinct populations.

1,145 citations

Journal ArticleDOI
TL;DR: It is shown that LT-HSCs utilize glycolysis instead of mitochondrial oxidative phosphorylation to meet their energy demands and that Meis1 regulates HSC metabolism through transcriptional activation of Hif-1alpha.

920 citations