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Early development and functional properties of tryptase/chymase double-positive mast cells from human pluripotent stem cells
Guohui Bian1 , Yanzheng Gu3,4 , Changlu Xu2 , Wenyu Yang2 , Xu Pan1 , Yijin Chen1 , Mowen Lai1 , Ya Zhou1 , Yong Dong1 , Bin Mao1 , Qiongxiu Zhou1 , Bo Chen1 , Tatsutoshi Nakathata3,4 , Lihong Shi2 , Min Wu5 , Yonggang Zhang1,* , Feng Ma1,2,*
1Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Chengdu 610052, China
2State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, CAMS & PUMC, Tianjin 300020, China
3Stem Cell Key Laboratory of Jiangsu Province, Institute of Medical Biotechnology, Suzhou University, Suzhou 215123, China
4Stem Cell Key Laboratory of Jiangsu Province, Institute of Medical Biotechnology, Suzhou University, Suzhou 215123, China
5Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND 58203, US
*Correspondence to:Yonggang Zhang , Feng Ma ,
J Mol Cell Biol, Volume 13, Issue 2, February 2021, 104-115,
Keyword: mast cells, human pluripotent stem cells (hPSCs), development, tryptase, chymase

Mast cells (MCs) play a pivotal role in the hypersensitivity reaction by regulating the innate and adaptive immune responses. Humans have two types of MCs. The first type, termed MCTC, is found in the skin and other connective tissues and expresses both tryptase and chymase, while the second, termed MCT, which only expresses tryptase, is found primarily in the mucosa. MCs induced from human adult-type CD34+ cells are reported to be of the MCT type, but the development of MCs during embryonic/fetal stages is largely unknown. Using an efficient coculture system, we identified that a CD34+c-kit+ cell population, which appeared prior to the emergence of CD34+CD45+ hematopoietic stem and progenitor cells (HSPCs), stimulated robust production of pure Tryptase+Chymase+ MCs (MCTCs). Single-cell analysis revealed dual development directions of CD34+c-kit+ progenitors, with one lineage developing into erythro-myeloid progenitors (EMP) and the other lineage developing into HSPC. Interestingly, MCTCs derived from early CD34+c-kit+ cells exhibited strong histamine release and immune response functions. Particularly, robust release of IL-17 suggested that these early developing tissue-type MCTCs could play a central role in tumor immunity. These findings could help elucidate the mechanisms controlling early development of MCTCs and have significant therapeutic implications.