{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T14:42:19Z","timestamp":1790520139506,"version":"4.1.0"},"reference-count":55,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T00:00:00Z","timestamp":1634688000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["18H03998"],"award-info":[{"award-number":["18H03998"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,11,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Most lineages of blood cells, including immune cells, are generated from hematopoietic stem cells (HSCs) in bone marrow throughout adult life. Since HSCs cannot expand on their own, they require and contact the special microenvironments, termed niches for their maintenance. HSC niches comprise supportive cells that provide adjacent HSCs with critical signals, including cytokines. Although bone marrow microenvironments have been thought to be complex, recent studies have demonstrated that the bone marrow-specific population of fibroblastic reticular cells with long processes, termed CXC chemokine ligand 12 (CXCL12)-abundant reticular (CAR) cells, which overlap strongly with leptin receptor (LepR)-expressing (LepR+) cells, is the major cellular component of niches for HSCs and lymphoid progenitors. CAR cells have salient features, expressing much higher levels of critical HSC niche factors than any other cell populations and function as self-renewing mesenchymal stem cells. Human counterpart of CAR cells is present and affected in diseases, including leukemia. Foxl1+ telocytes recently identified as the niche for intestinal stem cells share some features with CAR cells, suggesting that CAR cells might serve as a prototype for fibroblastic reticular cells creating niche for long-lived cells, including tissue stem cells and memory lymphocytes. These findings provided the basis for future mechanistic studies on the cross-talk between hematopoietic cells and microenvironments in both health and disease.<\/jats:p>","DOI":"10.1093\/intimm\/dxab092","type":"journal-article","created":{"date-parts":[[2021,10,19]],"date-time":"2021-10-19T13:51:25Z","timestamp":1634651485000},"page":"821-826","source":"Crossref","is-referenced-by-count":14,"title":["Identification of microenvironmental niches for hematopoietic stem cells and lymphoid progenitors\u2014bone marrow fibroblastic reticular cells with salient features"],"prefix":"10.1093","volume":"33","author":[{"given":"Yoshiki","family":"Omatsu","sequence":"first","affiliation":[{"name":"Laboratory of Stem Cell Biology and Developmental Immunology, Graduate School of Frontier Biosciences and Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University , Osaka , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Nagasawa","sequence":"additional","affiliation":[{"name":"Laboratory of Stem Cell Biology and Developmental Immunology, Graduate School of Frontier Biosciences and Graduate School of Medicine, WPI Immunology Frontier Research Center, Osaka University , Osaka , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,10,20]]},"reference":[{"key":"2022070618471396500_CIT0001","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1038\/nature02041","article-title":"Identification of the haematopoietic stem cell niche and control of the niche size","volume":"425","author":"Zhang","year":"2003","journal-title":"Nature"},{"key":"2022070618471396500_CIT0002","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1038\/nature02040","article-title":"Osteoblastic cells regulate the haematopoietic stem cell niche","volume":"425","author":"Calvi","year":"2003","journal-title":"Nature"},{"key":"2022070618471396500_CIT0003","doi-asserted-by":"crossref","first-page":"2678","DOI":"10.1182\/blood-2014-06-582924","article-title":"Osteoblast ablation reduces normal long-term hematopoietic stem cell self-renewal but accelerates leukemia development","volume":"125","author":"Bowers","year":"2015","journal-title":"Blood"},{"key":"2022070618471396500_CIT0004","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1084\/jem.20141843","article-title":"Specific bone cells produce DLL4 to generate thymus-seeding progenitors from bone marrow","volume":"212","author":"Yu","year":"2015","journal-title":"J. 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Haematol."},{"key":"2022070618471396500_CIT0044","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1016\/j.stem.2019.02.018","article-title":"Mesenchymal niche-specific expression of Cxcl12 controls quiescence of treatment-resistant leukemia stem cells","volume":"24","author":"Agarwal","year":"2019","journal-title":"Cell Stem Cell"},{"key":"2022070618471396500_CIT0045","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/j.ccr.2012.02.018","article-title":"Altered microenvironmental regulation of leukemic and normal stem cells in chronic myelogenous leukemia","volume":"21","author":"Zhang","year":"2012","journal-title":"Cancer Cell"},{"key":"2022070618471396500_CIT0046","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1038\/ncb3530","article-title":"Leptin-receptor-expressing bone marrow stromal cells are myofibroblasts in primary myelofibrosis","volume":"19","author":"Decker","year":"2017","journal-title":"Nat. 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