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A new mechanism of hematopoietic stem cell expansion identified
[ 2017-08-11 ]

The allusion of mencius’ mother moving three time tells us that a proper environment is particularly important for children’s growing up. In the case of hematopoietic stem and progenitor cells (HSPCs), the microenvironment is dynamic in vivo during HSPC development. For example, HSPCs first emerge from hemogenic endothelium in the aorta-gonad-mesonephros region, and then expand in the caudal hematopoietic tissue (CHT) in fish or fetal liver (FL) in mammals, and finally home to the kidney (fish) or the bone marrow (mammals) to sustain adult life. All of these findings indicate that specific niches are important for HSPC development at various stages. However, the mechanism of how niche regulates HSPC expansion remains incompletely understood.

Using zebrafish as a model, the Hematopoiesis and Cardiovascular Development Group led by Prof. Feng Liu, found that the developing HSPCs closely associate with the dynamic vascular niche in the zebrafish CHT through observing the HSPC behavior in vivo by confocal microscopy. They also noticed that the caudal vein orients the proliferation and migration of HSPCs, indicating that vascular endothelial cells may play an important role in the CHT. RNA-Sequencing with sorted cells from the CHT revealed an endothelial-specific transcription factor, Krüppel-like factor 6a (Klf6a). klf6a deficiency led to defective CHT vascular niche that failed to support HSPC lodgement and expansion. Furthermore, they identified that Klf6a promotes HSPC maintenance through Ccl25b-Ccr7 chemokine signaling. To investigate whether Ccl25b, which is homologous to mammalian Ccl21, plays an evolutionarily conserved role in mammals, they performed the ex vivo culture experiments with the Lin-Sca-1+c-Kit cells sorted from mouse FL. The culture experiment results supported the conserved role of Ccl21/Ccr7 signaling in promoting FL HSPC expansion in mammals. In summary, these results provide a new layer of understanding of definitive hematopoiesis in vertebrates including mammals, and may also have implications for in vitro HSPC expansion and HSPC engraftment after transplantation.

This study was published online in Developmental Cell on Aug 10, 2017. This work was supported by grants from the National Natural Science Foundation of China (31425016, 81530004), and the Ministry of Science and Technology of China (2016YFA0100500).

Websitehttp://www.cell.com/developmental-cell/fulltext/S1534-5807(17)30554-3

Figure 1: Model for development of HSPCs in the CHT niche. Klf6a+ vascular ECs can produce ccl25b that attracts HSPCs to settle closely to the caudal vein, and perivascular ECs are triggered by an arriving HSPC to form an EC pocket. Later, HSPC proliferate in the stem cell pocket in the CHT niche. The orange cells indicate perivascular ECs and green cells indicate HSPCs. The red plots mark chemokine ligand (ccl25b).

Figure 2. An artistic drawing of a Chinese allusion about Mencius's mother moving, in which a wise mother moved three times in order to get her son a better learning environment. Mencius (HSC, hematopoietic stem cell) gradually concentrated on learning after he settled down near a school (CHT niche) following her mother (chemokine). Later, Mencius became a great saint in Chinese history. Art by Yuanyuan Xue and Feng Liu.

 

 

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