Understanding the Journey of Human Hematopoietic Stem Cell Development

Abstract

Hematopoietic stem cells (HSCs) surface during embryogenesis leading to the genesis of the hematopoietic system, which is vital for immune function, homeostasis balance, and inflammatory responses in the human body. Hematopoiesis is the process of blood cell formation, which initiates from hematopoietic stem/progenitor cells (HSPCs) and is responsible for the generation of all adult blood cells. With their self-renewing and pluripotent properties, human pluripotent stem cells (hPSCs) provide an unprecedented opportunity to create in vitro models of differentiation that will revolutionize our understanding of human development, especially of the human blood system. The utilization of hPSCs provides newfound approaches for studying the origins of human blood cell diseases and generating progenitor populations for cell-based treatments. Current shortages in our knowledge of adult HSCs and the molecular mechanisms that control hematopoietic development in physiological and pathological conditions can be resolved with better understanding of the regulatory networks involved in hematopoiesis, their impact on gene expression, and further enhance our ability to develop novel strategies of clinical importance. In this review, we delve into the recent advances in the understanding of the various cellular and molecular pathways that lead to blood development from hPSCs and examine the current knowledge of human hematopoietic development. We also review how in vitro differentiation of hPSCs can undergo hematopoietic transition and specification, including major subtypes, and consider techniques and protocols that facilitate the generation of hematopoietic stem cells.

Figure 1

Embryonic hematopoiesis. Establishment of primitive and definitive HSCs during embryonic development.

Figure 2

Hematopoietic differentiation from hPSCs. Schematic summary of reported strategies for hematopoietic differentiation from hPSCs. Human PSCs can be differentiated into hematopoietic cells (HSCs) by three strategies: OP9 coculture, direct differentiation, and transcription-mediated differentiation approach.

Figure 3

Established stages of hematopoietic development from hPSCs⁺. The primitive mesodermal precursors are capable of forming mesenchymoangioblast (MB) and hemangioblast (HB) in the presence of FGF2 [62, 122, 125]. Mesodermal commitment to angiohematopoietic development progressively leads to the formation of ^EMHlin⁻KDR^brightAPLNR⁺PDGFRa^low/− hematovascular mesodermal precursors (HVMPs) [62, 89]. The HEP stage was identified based on the expression of the typical endothelial markers VE-cadherin, CD31, and CD34 and the absence of the panhematopoietic marker CD43 [62, 88]. HE cells were distinguished from non-HE cells based on the presence of CD73 expression [62, 132]. Initial hematopoietic progenitors arising from the VE-cadherin+ population show the presence of CD235a, low levels of CD43, and absence of CD41a expression. These cells can form hematopoietic colonies in the presence of FGF2 and retain their endothelial potential. These progenitors were labelled as angiogenic hematopoietic progenitors (AHPs) [62, 132]. Progressive hematopoietic development is identified by the appearance of CD43 expression, and all hematopoietic CFCs are accumulated in this fraction. Distinct subsets of CD43⁺ hematopoietic cells, including CD41a⁺CD235a⁺ erythromegakaryocytic progenitors and lin−CD34⁺CD43⁺CD45^+/− multipotent myelolymphoid progenitors, are also established [63, 88, 89, 105].