{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T07:38:48Z","timestamp":1793777928847,"version":"4.6.1"},"reference-count":67,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"845","funder":[{"DOI":"10.13039\/501100009252","name":"Science for Life Laboratory","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009252","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100015701","name":"Uppsala Multidisciplinary Center for Advanced Computational Science","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100015701","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2025-03154"],"award-info":[{"award-number":["2025-03154"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2020-02025"],"award-info":[{"award-number":["2020-02025"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"crossref","award":["NNF25OC0105090"],"award-info":[{"award-number":["NNF25OC0105090"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"crossref"}]},{"name":"the ALF agreement between the Swedish government and county councils","award":["ALFGBG-1006264"],"award-info":[{"award-number":["ALFGBG-1006264"]}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2026,4,15]]},"abstract":"<jats:p>\n                    The cartilaginous growth plate is a critical organ responsible for longitudinal bone growth. It closes after puberty in humans but remains open throughout life in mice. Although cartilage stem cells have been identified in murine growth plates, their existence in humans and their regulation by growth hormone (GH), the most widely used therapy for growth retardation, remain unknown. Here, we characterized the cellular and molecular organization of early pubertal human growth plates using unique surgical specimens from growth-restricting procedures and examined their direct responsiveness to GH. Single-cell and spatial analyses revealed two distinct stemlike populations in the resting zone, differing in proliferative activity, molecular identity, and regulatory cues. The root stem cells express multiple skeletal stem cell markers but not parathyroid hormone\u2013related peptide and reside in a specialized microenvironment low in WNT and TGF-\u03b2 growth factors. A similar population was identified in transcriptionally profiled unsorted murine growth plates, and clonal lineage tracing demonstrated that these root cells, marked by expression of the\n                    <jats:italic toggle=\"yes\">Prrx1<\/jats:italic>\n                    gene, generate extensive chondrocyte clones and differentiate into stromal and osteoblastic lineages, confirming their stem cell properties. Human growth plate explant cultures showed that GH directly activates JAK\/STAT, TGF-\u03b2, and ERK intracellular signaling pathways, inhibits AKT signaling, and stimulates cartilage growth and proliferation of cartilage stem cells and chondrocytes in the proliferative zone. Together, these findings uncover a conserved dual stem cell organization in human and mouse growth plates and define direct mechanisms of GH action, providing a framework for optimizing growth-promoting therapies.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adw3590","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T17:58:17Z","timestamp":1776275897000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":4,"title":["A transcriptional atlas of the pubertal human growth plate reveals two populations of stem cells and direct effect of growth hormone"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8553-6880","authenticated-orcid":true,"given":"Nelson Tsz Long","family":"Chu","sequence":"first","affiliation":[{"name":"Centre for Bone and Arthritis Research, Institute of Medicine at the Sahlgrenska Academy, University of Gothenburg, Gothenburg 41345, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9939-6492","authenticated-orcid":true,"given":"Ostap","family":"Dregval","sequence":"additional","affiliation":[{"name":"Centre for Bone and Arthritis Research, Institute of Medicine at the Sahlgrenska Academy, University of Gothenburg, Gothenburg 41345, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1832-1051","authenticated-orcid":true,"given":"Farasat","family":"Zaman","sequence":"additional","affiliation":[{"name":"Department of Women\u2032s and Children\u2032s Health, Karolinska Institutet and Karolinska University Hospital, Stockholm 17177, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8026-3665","authenticated-orcid":true,"given":"Lei","family":"Li","sequence":"additional","affiliation":[{"name":"Centre for Bone and Arthritis Research, Institute of Medicine at the Sahlgrenska Academy, University of Gothenburg, Gothenburg 41345, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Tian","sequence":"additional","affiliation":[{"name":"Centre for Bone and Arthritis Research, Institute of Medicine at the Sahlgrenska Academy, University of Gothenburg, Gothenburg 41345, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Liu","sequence":"additional","affiliation":[{"name":"Centre for Bone and Arthritis Research, Institute of Medicine at the Sahlgrenska Academy, University of Gothenburg, Gothenburg 41345, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9472-6184","authenticated-orcid":true,"given":"Dana","family":"Trompet","sequence":"additional","affiliation":[{"name":"Centre for Bone and Arthritis Research, Institute of Medicine at the Sahlgrenska Academy, University of Gothenburg, Gothenburg 41345, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baoyi","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jussi O.","family":"Heinonen","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9633-2805","authenticated-orcid":true,"given":"Claes","family":"Ohlsson","sequence":"additional","affiliation":[{"name":"Centre for Bone and Arthritis Research, Institute of Medicine at the Sahlgrenska Academy, University of Gothenburg, Gothenburg 41345, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1067-4976","authenticated-orcid":true,"given":"Lars","family":"S\u00e4vendahl","sequence":"additional","affiliation":[{"name":"Department of Women\u2032s and Children\u2032s Health, Karolinska Institutet and Karolinska University Hospital, Stockholm 17177, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5471-0356","authenticated-orcid":true,"given":"Igor","family":"Adameyko","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden."},{"name":"Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Vienna 1090, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2696-5850","authenticated-orcid":true,"given":"Andrei S.","family":"Chagin","sequence":"additional","affiliation":[{"name":"Centre for Bone and Arthritis Research, Institute of Medicine at the Sahlgrenska Academy, University of Gothenburg, Gothenburg 41345, Sweden."},{"name":"Science for Life Laboratory, Institute of Medicine, University of Gothenburg, Gothenburg 41346, Sweden."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1210\/er.2009-0039"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1159\/000538016"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1159\/000327788"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01657"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11914-023-00827-1"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0662-5"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.165226"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-0989-6"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.64513"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1210\/er.2002-0033"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1203\/PDR.0b013e3181beaa8c"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.0301203"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2007-1581"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/235107a0"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.7079756"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.20.9826"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2512316122"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2018.22"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.13410"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41413-025-00407-2"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2010.01.373"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0414-6"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.55212"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btac746"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1677\/joe.0.174r001"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioadv\/vbac016"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4463"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.105536"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1136\/adc.77.4.319"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(96)70008-2"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.408963"},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.1002\/jor.24653"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.11.019"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-023-01131-x"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-024-02365-9"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.12.002"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03795-7"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41413-017-0005-4"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2019152118"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.11.042"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-024-01469-w"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1096\/fasebj.13.14.1985"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxlet.2013.10.020"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.1677\/JOE-09-0307"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.630248"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22179469"},{"key":"e_1_3_2_48_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells9061384"},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.15252\/msb.20209620"},{"key":"e_1_3_2_50_2","doi-asserted-by":"crossref","unstructured":"P. Rodriguez-Mier M. Garrido-Rodriguez A. Gabor J. Saez-Rodriguez Unified knowledge-driven network inference from omics data. bioRxiv 2024.10.26.620390 [Preprint] (2024). https:\/\/doi.org\/10.1101\/2024.10.26.620390.","DOI":"10.1101\/2024.10.26.620390"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06806-x"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.043281"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2004.08.004"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-30247-1"},{"key":"e_1_3_2_55_2","doi-asserted-by":"crossref","unstructured":"M. Avijgan A. R. L. Perez L. A. Galicia L. Sudupe J. G. Marchan-Alvarez A. Nazaraliyev \u017d. Andrusivov\u00e1 L. Larsson Y. Zhao F. Zaman H. Qian K. Blomgren F. Prosper J. N. Tegner J. Lundeberg L. S\u00e4vendahl R. Mirzazadeh D. Gomez-Cabrero P. T. Newton Human growth plates house resting zone sub-populations with features of quiescent stem cells. bioRxiv 2025.03.12.642613 [Preprint] (2025). https:\/\/doi.org\/10.1101\/2025.03.12.642613.","DOI":"10.1101\/2025.03.12.642613"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1180794"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06526-2"},{"key":"e_1_3_2_58_2","first-page":"157","article-title":"Endocrine regulation of the growth plate","volume":"64","author":"Nilsson O.","year":"2005","unstructured":"O. Nilsson, R. Marino, F. De Luca, M. Phillip, J. Baron, Endocrine regulation of the growth plate. Horm. Res. 64, 157\u2013165 (2005).","journal-title":"Horm. Res."},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bone.2021.116186"},{"key":"e_1_3_2_60_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0898-6568(01)00186-3"},{"key":"e_1_3_2_61_2","first-page":"51","article-title":"C-type natriuretic peptide analogs: Current and future therapeutic applications","volume":"98","author":"Galetaki D. M.","year":"2025","unstructured":"D. M. Galetaki, A. Dauber, C-type natriuretic peptide analogs: Current and future therapeutic applications. Horm. Res. Paediatr. 98, 51\u201358 (2025).","journal-title":"Horm. Res. Paediatr."},{"key":"e_1_3_2_62_2","doi-asserted-by":"publisher","DOI":"10.3390\/biom14010101"},{"key":"e_1_3_2_63_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41592-023-01943-7"},{"key":"e_1_3_2_64_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-020-0591-3"},{"key":"e_1_3_2_65_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae909"},{"key":"e_1_3_2_66_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad1025"},{"key":"e_1_3_2_67_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"e_1_3_2_68_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad347"}],"container-title":["Science Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/scitranslmed.adw3590","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T17:58:27Z","timestamp":1776275907000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/scitranslmed.adw3590"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,15]]},"references-count":67,"journal-issue":{"issue":"845","published-print":{"date-parts":[[2026,4,15]]}},"alternative-id":["10.1126\/scitranslmed.adw3590"],"URL":"https:\/\/doi.org\/10.1126\/scitranslmed.adw3590","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2025.03.14.642964","asserted-by":"object"}]},"ISSN":["1946-6234","1946-6242"],"issn-type":[{"value":"1946-6234","type":"print"},{"value":"1946-6242","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,15]]},"assertion":[{"value":"2025-01-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-20","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-25","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eadw3590"}}