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We show here that sirolimus enhanced regeneration of HSPCs in mice exposed to sublethal total body irradiation (TBI) and other regenerative stressors. Sorted Lin\u2212CD150+ bone marrow cells from sirolimus-treated TBI mice had increased expression of c-Kit and other hematopoietic genes. HSPCs from sirolimus-treated TBI mice were functionally competent when tested by competitive engraftment in vivo. Postradiation regeneration of HSPCs in mice treated with sirolimus was accompanied by decreased \u03b3-H2AX levels detected by flow cytometry and increased expression of DNA repair genes by quantitative polymerase chain reaction. Reduction of cell death and DNA damage post-radiation by sirolimus was associated with enhanced clearance of cellular reactive oxygen species (ROS) in HSPCs. Increased HSPC recovery with sirolimus was also observed in mice injected with hematoxic agents, busulfan and 5-fluorouracil. In contrast, sirolimus showed no effect on HSPCs in normal mice at steady state, but stimulated HSPC expansion in mice carrying the Wv mutation at the c-Kit locus. In human to mouse xenotransplantation, sirolimus enhanced engraftment of irradiated human CD34+ cells. In summary, our results are consistent with sirolimus' acceleration of HSPC recovery in response to hematopoietic stress, associated with reduced DNA damage and ROS. Sirolimus might have clinical application for the treatment and prevention of hematopoietic injury.<\/jats:p>","DOI":"10.1002\/stem.3313","type":"journal-article","created":{"date-parts":[[2021,11,26]],"date-time":"2021-11-26T06:52:08Z","timestamp":1637909528000},"page":"240-252","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Sirolimus augments hematopoietic stem and progenitor cell regeneration following hematopoietic insults"],"prefix":"10.1093","volume":"39","author":[{"given":"Zenghua","family":"Lin","sequence":"first","affiliation":[{"name":"Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA"},{"name":"Department of Hematology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maile K.","family":"Hollinger","sequence":"additional","affiliation":[{"name":"Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhijie","family":"Wu","sequence":"additional","affiliation":[{"name":"Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wanling","family":"Sun","sequence":"additional","affiliation":[{"name":"Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA"},{"name":"Department of Hematology, Xuanwu Hospital, Capital Medical University, Beijing, People's Republic of China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaylind","family":"Batey","sequence":"additional","affiliation":[{"name":"Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jisoo","family":"Kim","sequence":"additional","affiliation":[{"name":"Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jichun","family":"Chen","sequence":"additional","affiliation":[{"name":"Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8018-2366","authenticated-orcid":false,"given":"Xingmin","family":"Feng","sequence":"additional","affiliation":[{"name":"Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neal S.","family":"Young","sequence":"additional","affiliation":[{"name":"Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,12,12]]},"reference":[{"issue":"4","key":"2022022510531270200_stem3313-bib-0001","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1111\/j.1365-2141.1994.tb05107.x","article-title":"Effects of rhG-CSF, 5-fluorouracil and extramedullary irradiation on murine megakaryocytopoiesis in vivo","volume":"88","author":"Scheding","year":"1994","journal-title":"Br J Haematol"},{"issue":"12","key":"2022022510531270200_stem3313-bib-0002","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1016\/j.exphem.2003.08.014","article-title":"Ionizing radiation and busulfan inhibit murine bone marrow cell hematopoietic function via apoptosis-dependent and -independent mechanisms","volume":"31","author":"Meng","year":"2003","journal-title":"Exp Hematol"},{"issue":"1","key":"2022022510531270200_stem3313-bib-0003","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1111\/j.0959-9673.2006.00455.x","article-title":"Further development of a model of chronic bone marrow aplasia in the busulphan-treated mouse","volume":"87","author":"Turton","year":"2006","journal-title":"Int J Exp Pathol"},{"issue":"4","key":"2022022510531270200_stem3313-bib-0004","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.lfs.2004.10.080","article-title":"A novel polysaccharide of black soybean promotes myelopoiesis and reconstitutes bone marrow after 5-flurouracil- and irradiation-induced myelosuppression","volume":"77","author":"Liao","year":"2005","journal-title":"Life Sci"},{"issue":"10","key":"2022022510531270200_stem3313-bib-0005","doi-asserted-by":"crossref","first-page":"727","DOI":"10.7164\/antibiotics.28.727","article-title":"Rapamycin (AY-22,989), a new antifungal antibiotic. 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