A pyrimido-indole derivative promotes the differentiation of hematopoietic stem and progenitor cells from human-induced pluripotent stem cells by modulating YAP/Hippo signaling pathway
1
Issued Date
2025-11-15
Resource Type
ISSN
00142999
eISSN
18790712
Scopus ID
2-s2.0-105018089067
Pubmed ID
41052706
Journal Title
European Journal of Pharmacology
Volume
1007
Rights Holder(s)
SCOPUS
Bibliographic Citation
European Journal of Pharmacology Vol.1007 (2025)
Suggested Citation
Saleepimol P., Chaiyakitpattana G., Ongnok B., Phuwakanjana P., Chokpanuwat T., Chaiwijit P., Changkeb V., Yanukun K., Thongsin N., Wattanapanitch M., Asavapanumas N., Tubsuwan A., Sutjarit N., Hongeng S., Bhukhai K. A pyrimido-indole derivative promotes the differentiation of hematopoietic stem and progenitor cells from human-induced pluripotent stem cells by modulating YAP/Hippo signaling pathway. European Journal of Pharmacology Vol.1007 (2025). doi:10.1016/j.ejphar.2025.178208 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/112602
Title
A pyrimido-indole derivative promotes the differentiation of hematopoietic stem and progenitor cells from human-induced pluripotent stem cells by modulating YAP/Hippo signaling pathway
Corresponding Author(s)
Other Contributor(s)
Abstract
Hematopoietic stem and progenitor cell (HSPC) therapy effectively treats hematological disorders, such as hemoglobinopathies, aplastic anemia, and leukemias. However, limited HSPC availability and loss of stemness restrict clinical application, necessitating alternative sources. Human induced pluripotent stem cells (hiPSCs) offer promise due to their pluripotency and self-renewal. However, current protocols for generating HSPCs from hiPSCs often compromise their stemness and regenerative potential. This study investigates the potential of the pyrimido-indole derivative, specifically UM729, to enhance the production and functionality of HSPCs derived from hiPSCs. UM729 treatment significantly increased HSPC (CD34<sup>+</sup>CD45<sup>+</sup>CD90<sup>+</sup>) and long-term-HSC (CD34<sup>+</sup>CD38<sup>−</sup>CD45RA<sup>−</sup>CD90<sup>+</sup>CD49f<sup>+</sup>) markers compared with DMSO control, and promoted formation of hemogenic (CD144<sup>+</sup>CD73<sup>−</sup>) and vascular endothelial (CD144<sup>+</sup>CD73<sup>+</sup>) niche progenitors. The generated HSPCs demonstrated self-renewal capacity, confirmed by long-term culture-initiating cell (LTC-IC) assay. The expanded HSPCs retained long-term-HSC marker expression for up to seven days without detectable apoptosis and remained functionally responsive, as shown by lipopolysaccharide (LPS)-induced cytokine secretion. They differentiated into myeloid and erythroid lineages, with erythroid maturation confirmed by hemoglobin gene detection, expression of erythroid transcription factors, and normal cell morphology. Mechanistically, UM729 increased YAP protein levels, a key Hippo pathway regulator, predominantly in the cytoplasm, suggesting a potential effect on pathway inhibition. Co-treatment with UM729 and the YAP/TAZ inhibitor, dobutamine, further enhanced HSPC marker expression by up to 20-fold relative to DMSO control. These results demonstrate that UM729 supports scalable production of functional HSPCs from hiPSCs and that combination with Hippo pathway modulator may further improve yields. This approach holds promise for advancing hematopoietic stem cell–based therapies for blood diseases.