Defining early hematopoietic‐fated primitive streak specification of human pluripotent stem cells by the orchestrated balance of Wnt, activin, and BMP signaling. Issue 9 (10th February 2019)

• Record Type: Journal Article
• Authors: Shen, Jun; Lyu, Cuicui; Zhu, Yaoyao; Feng, Zicen; Zhang, Shuo; Hoyle, Dixie L.; Ji, Guangzhen; Brodsky, Robert A.; Cheng, Tao; Wang, Zack Z.
• Is Part Of: Journal of cellular physiology. Volume 234:Issue 9(2019:Sep.)
• Page Start: 16136
• Page End: 16147
• Publication Date: 2019-02-10
• Subjects: hematopoietic differentiation -- human pluripotent stem cells -- mesoderm -- primitive streak -- signaling pathways; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.28272
• Languages: English
• ISSNs: 0021-9541

Abstract

Abstract: Distinct regions of the primitive streak (PS) have diverse potential to differentiate into several tissues, including the hematopoietic lineage originated from the posterior region of PS. Although various signaling pathways have been identified to promote the development of PS and its mesoderm derivatives, there is a large gap in our understanding of signaling pathways that regulate the hematopoietic fate of PS. Here, we defined the roles of Wnt, activin, and bone morphogenetic protein (BMP) signaling pathways in generating hematopoietic‐fated PS from human pluripotent stem cells (hPSCs). We found that the synergistic balance of these signaling pathways was crucial for controlling the PS fate determination towards hematopoietic lineage via mesodermal progenitors. Although the induction of PS depends largely on the Wnt and activin signaling, the PS generated without BMP4 lacks the hematopoietic potential, indicating that the BMP signaling is necessary for the PS to acquire hematopoietic property. Appropriate levels of Wnt signaling is crucial for the development of PS and its specification to the hematopoietic lineage. Although the development of PS is less sensitive to activin or BMP signaling, the fate of PS to mesoderm progenitors and subsequent hematopoietic lineage is determined by appropriate levels of activin or BMP signaling. Collectively, our study demonstrates that Wnt, activin, and BMP signaling pathways play cooperative and distinct roles in regulating the fate determination of PS for hematopoietic development. Our understanding of the regulatory networks of hematopoietic‐fated PS would provide important insights into early hematopoietic patterning and possible guidance for generating functional hematopoietic cells from hPSCs in vitro. Abstract : Combined Wnt, activin/nodal, and bone morphogenetic protein (BMP) signaling effectively promote the formation of hematopoietic‐fated primitive streak (PS) and its hematopoietic specification. Increasing the levels of activin or BMP signaling will not affect the development of PS but display a strong posteriorizing effect on subsequent hematopoietic specification: High levels of activin signaling inhibit endothelial‐to‐hematopoietic transition without affecting mesoderm and hemogenic endothelial cell production, whereas high BMP signaling impairs PS‐derived mesoderm induction. High levels of Wnt signaling impair the development of PS and its subsequent hematopoietic transformation.