Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA.
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Institute of Materials Science and Nanotechnology, National Nanotechnology Research Center (UNAM), Bilkent University, 06800 Ankara, Turkey.
Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Department of Pathology, Massachusetts General Hospital Boston and Harvard Medical School, Boston, MA 02114, USA.
Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Dokuz Eylul University, Institute of Oncology, Department of Translational Oncology, Izmir, Turkey.
BioMicro Center at MIT, Department of Biology, MIT, Cambridge, MA 02139, USA.
Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Department of Biology, Siirt University, Science and Arts Faculty, 56100 Siirt, Turkey.
Department of Biology, MIT, Cambridge, MA 02139, USA.
Division of Comparative Medicine, Department of Biological Engineering, MIT, Cambridge, MA 02139, USA.
Dokuz Eylul University, Institute of Oncology, Department of Translational Oncology, Izmir, Turkey.
Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, MA 02139, USA.
Department of Pathology, Massachusetts General Hospital Boston and Harvard Medical School, Boston, MA 02114, USA.
Genomic Medicine Department, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH 43210 USA.
Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, MA 02139, USA.
Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA; Department of Biology, MIT, Cambridge, MA 02139, USA; Department of Pathology, Massachusetts General Hospital Boston and Harvard Medical School, Boston, MA 02114, USA; Klarman Cell Observatory, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: ohyilmaz@mit.edu.
Little is known about how metabolites couple tissue-specific stem cell function with physiology. Here we show that, in the mammalian small intestine, the expression of Hmgcs2 (3-hydroxy-3-methylglutaryl-CoA synthetase 2), the gene encoding the rate-limiting enzyme in the production of ketone bodies, including beta-hydroxybutyrate (βOHB), distinguishes self-renewing Lgr5+ stem cells (ISCs) from differentiated cell types. Hmgcs2 loss depletes βOHB levels in Lgr5+ ISCs and skews their differentiation toward secretory cell fates, which can be rescued by exogenous βOHB and class I histone deacetylase (HDAC) inhibitor treatment. Mechanistically, βOHB acts by inhibiting HDACs to reinforce Notch signaling, instructing ISC self-renewal and lineage decisions. Notably, although a high-fat ketogenic diet elevates ISC function and post-injury regeneration through βOHB-mediated Notch signaling, a glucose-supplemented diet has the opposite effects. These findings reveal how control of βOHB-activated signaling in ISCs by diet helps to fine-tune stem cell adaptation in homeostasis and injury.
