@article{120b49e31225453c8038ad01fe40235a,
title = "A latent subset of human hematopoietic stem cells resists regenerative stress to preserve stemness",
abstract = "Continuous supply of immune cells throughout life relies on the delicate balance in the hematopoietic stem cell (HSC) pool between long-term maintenance and meeting the demands of both normal blood production and unexpected stress conditions. Here we identified distinct subsets of human long-term (LT)-HSCs that responded differently to regeneration-mediated stress: an immune checkpoint ligand CD112lo subset that exhibited a transient engraftment restraint (termed latency) before contributing to hematopoietic reconstitution and a primed CD112hi subset that responded rapidly. This functional heterogeneity and CD112 expression are regulated by INKA1 through direct interaction with PAK4 and SIRT1, inducing epigenetic changes and defining an alternative state of LT-HSC quiescence that serves to preserve self-renewal and regenerative capacity upon regeneration-mediated stress. Collectively, our data uncovered the molecular intricacies underlying HSC heterogeneity and self-renewal regulation and point to latency as an orchestrated physiological response that balances blood cell demands with preserving a stem cell reservoir.",
author = "Kaufmann, {Kerstin B.} and Zeng, {Andy G.X.} and Etienne Coyaud and Laura Garcia-Prat and Efthymia Papalexi and Alex Murison and Laurent, {Estelle M.N.} and Michelle Chan-Seng-Yue and Gan, {Olga I.} and Kristele Pan and Jessica McLeod and H{\'e}l{\'e}na Boutzen and Sasan Zandi and Takayanagi, {Shin ichiro} and Rahul Satija and Brian Raught and Xie, {Stephanie Z.} and Dick, {John E.}",
note = "Funding Information: We thank the obstetrics units of Trillium Health and William Osler Health Partners for CB, the UHN-SickKids Flow cytometry facility for cell sorting, and M. Minden and the Leukemia Tissue Bank at Princess Margaret Cancer Centre/UHN for providing primary mPB samples. We thank E. Laurenti and all members of the laboratory of J.E.D., in particular J. C. Y. Wang, for critical feedback. This research was supported by the Deutsche Forschungsgemeinschaft (K.B.K.) and is part of the University of Toronto{\textquoteright}s Medicine by Design initiative, which receives funding from the Canada First Research Excellence Fund. Work in the laboratory of J.E.D. is supported by funds from the Princess Margaret Cancer Centre Foundation, the Canadian Institutes of Health Research (Foundation no. 154293 (to J.E.D), operating grant nos. 154293 and 89932 (to J.E.D), International Development Research Centre, Canadian Cancer Society (grant no. 703212 (to J.E.D)), Terry Fox Research Institute Program Project grant, Ontario Institute for Cancer Research through funding provided by the Government of Ontario, a Canada Research Chair and the Ontario Ministry of Health and Long Term Care. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2021",
month = jun,
doi = "10.1038/s41590-021-00925-1",
language = "English (US)",
volume = "22",
pages = "723--734",
journal = "Nature Immunology",
issn = "1529-2908",
publisher = "Nature Publishing Group",
number = "6",
}