Stem Cells

Wang, Shan; Mi, Rujia; Cai, Zhaopeng; Wang, Ziming; Zeng, Chenying; Xie, Zhongyu; Li, Jinteng; Ma, Mengjun; Liu, Wenjie; Su, Hongjun; Cen, Shuizhong; Wu, Yanfeng; Shen, Huiyong

doi: 10.1093/stmcls/sxac013pmid: 35403694

Abstract Bone marrow (BM) adipose tissue (BMAT), a unique adipose depot, plays an important role in diseases such as osteoporosis and bone metastasis. Precise control of mesenchymal stem cell (MSC) differentiation is critical for BMAT formation and regeneration. Here, we show that death associated protein kinase 1 (DAPK1) negatively regulates BM adipogenesis in vitro and in vivo. Prx1 creDapk1 loxp/loxp mice showed more adipocytes in the femur than Dapk1 loxp/loxp mice. Further mechanistic analyses revealed that DAPK1 inhibits p38 mitogen-activated protein kinase (MAPK) signaling in the nucleus by binding the p38 isoform MAPK14, decreasing p38 nuclear activity, which subsequently inhibits BM adipogenesis. The inhibitory effect of DAPK1 against MAPK14 was independent of its kinase activity. In addition, the decreased DAPK1 was observed in the BM-MSCs of ageing mice. Our results reveal a previously undescribed function for DAPK1 in the regulation of adipogenesis, and may also reveal the underlying mechanism of BMAT formation in ageing. Graphical Abstract Open in new tabDownload slide Graphical Abstract Open in new tabDownload slide BMAT, MSCs, DAPK1, MAPK14, Adipogenesis, Ageing This content is only available as a PDF. Author notes Shan Wang, Rujia Mi and Zhaopeng Cai have contributed equally to this work © The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected]. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Seong, Kyung-Joo; Choi, Seungho; Lee, Hyun-Gwan; Rhee, Joon Haeng; Lee, Jin Ho; Koh, Jeong-Tae; Kim, Sun-Hun; Choi, Won-Seok; Jung, Ji-Yeon; Kim, Won-Jae

doi: 10.1093/stmcls/sxab025pmid: 35304896

Ren, Jie; Wang, Xianli; Dong, Chuanming; Wang, Guangming; Zhang, Wenjun; Cai, Chunhui; Qian, Minxian; Yang, Danjing; Ling, Bin; Ning, Ke; Mao, Zhiyong; Liu, Baohua; Wang, Tinghua; Xiong, Liuliu; Wang, Wenyuan; Liang, Aibin;

Luo, Linjie; Santos, Andres; Konganti, Kranti; Hillhouse, Andrew; Lambertz, Isabel U; Zheng, Yuanning; Gunaratna, Ramesh T; Threadgill, David W; Fuchs-Young, Robin S

doi: 10.1093/stmcls/sxab018pmid: 35356986

Abstract Insulin-like growth factor I (IGF-1) has been implicated in breast cancer due to its mitogenic and anti-apoptotic effects. Despite substantial research on the role of IGF-1 in tumor progression, the relationship of IGF-1 to tissue stem cells, particularly in mammary tissue, and the resulting tumor susceptibility has not been elucidated. Previous studies with the BK5.IGF-1 transgenic (Tg) mouse model reveals that IGF-1 does not act as a classical, post-carcinogen tumor promoter in the mammary gland. Pre-pubertal Tg mammary glands display increased numbers and enlarged sizes of terminal end buds, a niche for mammary stem cells (MaSCs). Here we show that MaSCs from both wild type (WT) and Tg mice expressed IGF-1R and that overexpression of Tg IGF-1 increased numbers of MaSCs by undergoing symmetric division, resulting in an expansion of the MaSC and luminal progenitor (LP) compartments in pre-pubertal female mice. This expansion was maintained post-pubertally and validated by mammosphere assays in vitro and transplantation assays in vivo. The addition of recombinant IGF-1 promoted, and IGF-1R downstream inhibitors decreased mammosphere formation. Single-cell transcriptomic profiles generated from two related platforms reveal that IGF-1 stimulated quiescent MaSCs to enter the cell cycle and increased their expression of genes involved in proliferation, plasticity, tumorigenesis, invasion, and metastasis. This study identifies a novel, pro-tumorigenic mechanism, where IGF-1 increases the number of transformation-susceptible carcinogen targets during the early stages of mammary tissue development, and “primes” their gene expression profiles for transformation. Graphical Abstract Open in new tabDownload slide Graphical Abstract Open in new tabDownload slide Insulin-Like Growth Factor I, Stem Cells, Breast Neoplasms, Animal Models This content is only available as a PDF. © The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected]. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)