Notch signaling and the emergence of hematopoietic stem cells

• Published in: Developmental dynamics Vol. 249; no. 11; pp. 1302 - 1317
• Main Authors: Lomelí, Hilda, Castillo‐Castellanos, Francisco
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.11.2020; Wiley Subscription Services, Inc
• Subjects: Blood cells; Cell differentiation; definitive hematopoiesis; embryonic development; Embryos; endothelial cell; Endothelium; Evolutionary conservation; Hematology; Hematopoiesis; Hematopoietic stem cells; mammals; Molecular modelling; notch signaling; Pluripotency; Rodents; Signaling; Stem cell transplantation; Stem cells; Transgenic mice; Transplantation; Vertebrates; Zebrafish; definitive hematopoiesis; zebrafish; mammals; embryonic development; endothelial cell; notch signaling
• ISSN: 1058-8388; 1097-0177; 1097-0177
• DOI: 10.1002/dvdy.230

The hematopoietic stem cell (HSC) is able to give rise to all blood cell lineages in vertebrates. HSCs are generated in the early embryo after two precedent waves of primitive hematopoiesis. Canonical Notch signaling is at the center of the complex mechanism that controls the development of the definitive HSC. The successful in vitro generation of hematopoietic cells from pluripotent stem cells with the capacity for multilineage hematopoietic reconstitution after transplantation requires the recapitulation of the most important process that takes place in the hemogenic endothelium during definitive hematopoiesis, that is the endothelial‐to‐hematopoietic transition (EHT). To meet this challenge, it is necessary to thoroughly understand the molecular mechanisms that modulate Notch signaling during the HSC differentiation process considering different temporal and spatial dimensions. In recent years, there have been important advances in this field. Here, we review relevant contributions describing different genes, factors, environmental cues, and signaling cascades that regulate the EHT through Notch interactions at multiple levels. The evolutionary conservation of the hematopoietic program has made possible the use of diverse model systems. We describe the contributions of the zebrafish model and the most relevant ones from transgenic mouse studies and from in vitro differentiated pluripotent cells. Key Findings The main subject of our review is the endothelial‐to‐hematopoietic transition, a step that takes place in the hemogenic endothelium and is dependent on the activation of Notch signaling. We discuss the relevant contributions of the molecular mechanisms that interact with Notch signals at multiple levels, including ligand‐receptor pair engagements, the receptor trafficking, the nuclear context, the tissue architectures, and the cross‐talk with other regulatory networks. With this analysis, we deciphered the complexity of the Notch signaling, which involves different simultaneous actions or in short time windows occurring in cell‐autonomous and non‐autonomous fashions.