The significance and application of vascular niche in the development and maintenance of hematopoietic stem cells
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Deriving hematopoietic stem cells (HSCs) from human pluripotent stem cells is one of major goals in stem cell and hematological research. To induce HSCs from human pluripotent stem cells, many attempts to mimic embryonic development through stepwise exposure to morphogens. HSCs arise from dorsal aorta of embryos then migrate and settle in the bone marrow. Development and maintenance of HSCs are controlled by the microenvironmental cues around the blood vessels (called vascular niche) through morphogens and cytokines. Vascular niche serves as a common mechanism from embryo development to life-long maintenance of HSCs. In this chapter, I discuss that how vascular niche regulates development and maintenance of HSCs and exemplify the role of vascular niche to exquisitely induce HSCs from human pluripotent stem cells.
KeywordsHematopoietic stem cell Pluripotent stem cell Niche Transcriptional regulation Signaling
The development and maintenance of HSCs is controlled by a microenvironment called vascular niche via signal transduction . HSCs develop from a specific subset of hemogenic endothelial cells in aortic wall of embryos. Vascular endothelial cells and surrounding mesenchymal and neural cells form vascular niche facilitate conversion of hemogenic endothelial cells to HSCs through morphogens and cytokines. HSCs develop in dorsal aorta then migrate and expand in fetal liver, and finally settle down in bone marrow. Through the entire processes, the vascular niche regulates HSCs via morphogens and cytokines. The evidence of vascular niche was initially demonstrated by Morrison et al. , further supported by Nagasawa and Frenette [3, 4]. Independently, Li et al. proposed an osteoblast niche, but the role of osteoblastic cells in regulation of HSCs was called under question (see Sugimura review  for details). In this chapter, I introduce the role of vascular niche in the development and maintenance of HSCs and exemplify the application of vascular niche to induce HSCs from human pluripotent stem cells.
The role of vascular niche in the development of hematopoietic stem cells
The role of vascular niche in maintenance of hematopoietic stem cells
Once HSCs were specified from embryos or derived from human pluripotent stem cells, they should to be maintained in vascular niche through proper combination of signaling factors. Vascular niche in bone marrow provide cytokine milieu to HSCs (Fig. 1). There are two approaches to understand how vascular niche maintain HSCs. A genetic approach using a niche cell specific Cre mouse model revealed that the cytokines SCF and CXCL12 are produced from both vascular niche endothelial cells and mesenchymal stromal cells, and these are responsible for the maintenance of HSCs. The role of various cytokines is elucidated using the same approach. For example, IL7 was produced from vascular niche endothelial cells and mesenchymal stromal cells, and involved in lymphocyte differentiation, but not in maintenance of HSCs . Indeed, IL7 has been used as one of major factors to differentiate lymphocytes from HSCs. In contrast to mouse HSCs for which genetic model is available, elucidating factors that maintain human HSCs has been still challenging. Identifying such factors will be a crucial milestone to derive HSCs from human pluripotent stem cells. Recent researches showed that compounds called SR1 and UM171 maintain and expand human HSCs in culture . SR1 is an antagonist of allyl hydrocarbon receptors, and its precise downstream mechanism is remained clear. The target of UM 171 is also not clear. By elucidating exquisite molecular logic of these compounds, it will be possible to employ them to maintain HSCs derived from human pluripotent stem cells. Another expected approach to understand the role of vascular niche in HSC maintenance is reconstruction of human bone marrow microenvironment . This approach undertakes reconstitution of vascular niche by implanting human endothelial and mesenchymal progenitors to form ectopic human vascular niche in mouse, follow by transplantation of human HSCs. Identification of factors that maintain human HSCs will revolutionize current attempts to derive HSCs from human pluripotent stem cells. To overcome the current shortness of understanding in morphogens and cytokines from vascular niche, I took a complimentary approach to induce transcription factors (RUNX1, HOXA, SPI1, ERG, etc.), master regulators of HSC development, to hemogenic endothelial cells to convert to HSCs.
Application of vascular niche—induction of hematopoietic stem cells from human pluripotent stem cells
Factors from vascular niche applied in inducing hematopoietic stem cells
Induction from human pluripotent stem cells (Daley)
Induction from adult murine endothelial cells (Rafii)
Ventral wall of dorsal aorta
Morphogens (NOTCH, HEDGHOG, WNT), Transcription factors (RUNX1, SPI1 etc.)
Morphogens + transcription factors (RUNX1, SPI1 + 5 TFs)
Transcription factors (RUNX1, SPI1 + 2 TFs)
Sinusoid of BM
Cytokines (SCF, CXCL12 etc.)
Autochthonous specification in BM
Co-culture with vascular niche cells
In this chapter I reviewed the vascular niche that is responsible for the development and maintenance of HSCs and exemplified how vascular niche plays a crucial role in derivation of HSCs from human pluripotent stem cells. An ultimate goal is to exquisitely reconstruct morphogens and cytokines milieu from vascular niche to specify and maintain HSCs. Future research aims to identify morphogens and cytokines produced by vascular niche and to induce HSCs entirely in vitro.