TY - JOUR
T1 - Self-renewal of a purified Tie2+ hematopoietic stem cell population relies on mitochondrial clearance
AU - Ito, Kyoko
AU - Turcotte, Raphaël
AU - Cui, Jinhua
AU - Zimmerman, Samuel E.
AU - Pinho, Sandra
AU - Mizoguchi, Toshihide
AU - Arai, Fumio
AU - Runnels, Judith M.
AU - Alt, Clemens
AU - Teruya-Feldstein, Julie
AU - Mar, Jessica C.
AU - Singh, Rajat
AU - Suda, Toshio
AU - Lin, Charles P.
AU - Frenette, Paul S.
AU - Ito, Keisuke
N1 - Funding Information:
We thank all members of the Ito lab and Einstein Stem Cell Institute for their comments on HSC self-renewal and M. Wolfgang, A. Carracedo, H. You, and the Einstein Flow Cytometry and Analytical Imaging core facilities (grant P30CA013330) for help and materials. This work was supported by NIH (grants R01DK98263 and R01DK100689 to Ke.I.) and NYSTEM (New York State Stem Cell Science single-cell-core, grant C029154 to Ke.I.), Harvard Stem Cell Institute (to C.P.L.), NIH and Ellison Medical Foundation (to R.S.), NIH and Leukemia Lymphoma Society (to P.S.F.), and Japan Society for the Promotion of Science (to T.S.). We declare no competing financial interests.
Publisher Copyright:
© 2016, American Association for the Advancement of Science. All rights reserved.
PY - 2016/12/2
Y1 - 2016/12/2
N2 - A single hematopoietic stem cell (HSC) is capable of reconstituting hematopoiesis and maintaining homeostasis by balancing self-renewal and cell differentiation. The mechanisms of HSC division balance, however, are not yet defined. Here we demonstrate, by characterizing at the single-cell level a purified and minimally heterogeneous murine Tie2+ HSC population, that these top hierarchical HSCs preferentially undergo symmetric divisions. The induction of mitophagy, a quality control process in mitochondria, plays an essential role in self-renewing expansion of Tie2+ HSCs. Activation of the PPAR (peroxisome proliferator-activated receptor)-fatty acid oxidation pathway promotes expansion of Tie2+ HSCs through enhanced Parkin recruitment in mitochondria. These metabolic pathways are conserved in human TIE2+ HSCs. Our data thus identify mitophagy as a key mechanism of HSC expansion and suggest potential methods of cell-fate manipulation through metabolic pathways.
AB - A single hematopoietic stem cell (HSC) is capable of reconstituting hematopoiesis and maintaining homeostasis by balancing self-renewal and cell differentiation. The mechanisms of HSC division balance, however, are not yet defined. Here we demonstrate, by characterizing at the single-cell level a purified and minimally heterogeneous murine Tie2+ HSC population, that these top hierarchical HSCs preferentially undergo symmetric divisions. The induction of mitophagy, a quality control process in mitochondria, plays an essential role in self-renewing expansion of Tie2+ HSCs. Activation of the PPAR (peroxisome proliferator-activated receptor)-fatty acid oxidation pathway promotes expansion of Tie2+ HSCs through enhanced Parkin recruitment in mitochondria. These metabolic pathways are conserved in human TIE2+ HSCs. Our data thus identify mitophagy as a key mechanism of HSC expansion and suggest potential methods of cell-fate manipulation through metabolic pathways.
UR - http://www.scopus.com/inward/record.url?scp=84991108288&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84991108288&partnerID=8YFLogxK
U2 - 10.1126/science.aaf5530
DO - 10.1126/science.aaf5530
M3 - Article
C2 - 27738012
AN - SCOPUS:84991108288
SN - 0036-8075
VL - 354
SP - 1156
EP - 1160
JO - Science
JF - Science
IS - 6316
ER -