PMID- 31552804 OWN - NLM STAT- MEDLINE DCOM- 20200803 LR - 20220716 IS - 1557-8534 (Electronic) IS - 1547-3287 (Print) IS - 1547-3287 (Linking) VI - 28 IP - 22 DP - 2019 Nov 15 TI - In Vitro Expansion of Hematopoietic Stem Cells by Inhibition of Both GSK3 and p38 Signaling. PG - 1486-1497 LID - 10.1089/scd.2019.0119 [doi] AB - Hematopoietic stem cell (HSC) transplantation therapy is one of the most effective treatments for life-threatening hematopoietic diseases. Bone marrow (BM) and mobilized peripheral blood are the major sources of HSCs, but these resources are limited by a paucity of human leukocyte antigen (HLA)-matched donors. Umbilical cord blood (UCB) is the most promising alternative to obtain HSCs for transplantation therapy. However, UCB transplantation therapy is limited by low numbers of HSCs per unit of UCB. In vitro HSC expansion is believed to be the most effective and applicable strategy to address this issue. Here we report that a moderate concentration of GSK3 inhibitor promotes HSC expansion by inducing moderate levels of beta-catenin activity in HSCs. However, such a concentration of GSK3 inhibitor also stimulates myeloid cells to produce inflammatory cytokines, which attenuate HSC expansion by inducing p38 activation. Thus, when unpurified HSCs were used in culture, inhibition of p38-induced inflammatory cytokine signaling was required to ensure HSC expansion induced by the low concentration of GSK3 inhibitor. Our study suggests that the combination of a moderate concentration of p38 inhibitor plus a GSK3 inhibitor synergistically promotes the expansion of both murine BM HSCs and human UCB HSCs. FAU - Li, Jing AU - Li J AD - Department of Biology, College of Life Sciences, Shanghai Normal University, Shanghai, China. FAU - Zhang, Lei AU - Zhang L AD - Department of Biology, College of Life Sciences, Shanghai Normal University, Shanghai, China. AD - Department of Cancer Biology, Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, Illinois. FAU - Yin, Lizhi AU - Yin L AD - Department of Biology, College of Life Sciences, Shanghai Normal University, Shanghai, China. FAU - Ma, Na AU - Ma N AD - Department of Biology, College of Life Sciences, Shanghai Normal University, Shanghai, China. FAU - Wang, Tian AU - Wang T AD - Department of Biology, College of Life Sciences, Shanghai Normal University, Shanghai, China. FAU - Wu, Yuanyuan AU - Wu Y AD - Department of Biology, College of Life Sciences, Shanghai Normal University, Shanghai, China. FAU - Wang, Ming AU - Wang M AD - Department of Biology, College of Life Sciences, Shanghai Normal University, Shanghai, China. FAU - Yang, Xingxing AU - Yang X AD - Department of Biology, College of Life Sciences, Shanghai Normal University, Shanghai, China. FAU - Xu, Hui AU - Xu H AD - Department of Biology, College of Life Sciences, Shanghai Normal University, Shanghai, China. FAU - Hao, Caiqin AU - Hao C AD - Department of Biology, College of Life Sciences, Shanghai Normal University, Shanghai, China. FAU - Li, Wenyan AU - Li W AD - Department of Gynaecology and Obstetrics, Lanzhou University Second Hospital, Lanzhou, China. FAU - Wei, Wei AU - Wei W AD - Department of Cancer Biology, Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, Illinois. FAU - Xu, Yan AU - Xu Y AD - Department of Biology, College of Life Sciences, Shanghai Normal University, Shanghai, China. FAU - Zhang, Feng AU - Zhang F AD - Department of Biology, College of Life Sciences, Shanghai Normal University, Shanghai, China. FAU - Breslin, Peter AU - Breslin P AD - Department of Cancer Biology, Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, Illinois. AD - Department of Biology, Loyola University Chicago, Chicago, Illinois. AD - Department of Molecular/Cellular Physiology, Loyola University Chicago, Chicago, Illinois. FAU - Zhang, Jiwang AU - Zhang J AD - Department of Cancer Biology, Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, Illinois. AD - Department of Pathology, Loyola University Medical Center, Maywood, Illinois. FAU - Zhang, Jun AU - Zhang J AD - Department of Biology, College of Life Sciences, Shanghai Normal University, Shanghai, China. LA - eng GR - R01 CA223194/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20191029 PL - United States TA - Stem Cells Dev JT - Stem cells and development JID - 101197107 RN - 0 (HLA Antigens) RN - 9005-49-6 (Heparin) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) RN - EC 2.7.11.26 (Glycogen Synthase Kinase 3) SB - IM MH - Animals MH - Bone Marrow Cells/cytology MH - Bone Marrow Transplantation MH - Cell Differentiation/genetics MH - Cell Proliferation/drug effects MH - Drug Synergism MH - Fetal Blood/cytology/*transplantation MH - Glycogen Synthase Kinase 3/antagonists & inhibitors/*genetics MH - HLA Antigens/genetics MH - Hematologic Neoplasms/genetics/immunology/*therapy MH - *Hematopoietic Stem Cell Transplantation MH - Hematopoietic Stem Cells/cytology MH - Heparin/pharmacology MH - Humans MH - Mice MH - Signal Transduction MH - p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors/*genetics PMC - PMC9208333 OTO - NOTNLM OT - GSK3 OT - HSCs OT - UCB OT - p38 OT - beta-catenin COIS- No competing financial interests exist. EDAT- 2019/09/26 06:00 MHDA- 2020/08/04 06:00 PMCR- 2020/11/15 CRDT- 2019/09/26 06:00 PHST- 2019/09/26 06:00 [pubmed] PHST- 2020/08/04 06:00 [medline] PHST- 2019/09/26 06:00 [entrez] PHST- 2020/11/15 00:00 [pmc-release] AID - 10.1089/scd.2019.0119 [pii] AID - 10.1089/scd.2019.0119 [doi] PST - ppublish SO - Stem Cells Dev. 2019 Nov 15;28(22):1486-1497. doi: 10.1089/scd.2019.0119. Epub 2019 Oct 29.