Research is achieved in body weight programming to regenerate hematopoietic stem cell-like cells

Hoxb5 reprogramms MPP into HSC-like cells. Courtesy of the research group

Wang Jinyong’s research group at the Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, studied the realization of regenerative hematopoietic stem cell-like cells in weight programming. The study was recently published online in Cell Proliferation. Huang Dehao, a doctoral student at the Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, and Zhao Qianhao, an associate researcher at the School of Medicine of Sun Yat-sen University, are the co-first authors of the paper, and postdoctoral fellows Hu Fangxiao and Wang Jinyong are co-corresponding authors. The research was supported and assisted by Cheng Hui’s team at the State Key Laboratory of Experimental Hematology.

The study revealed for the first time that Hoxb5 can efficiently induce multipotent blood progenitors (MPP) to reprogram into novel cells with hematopoietic stem cell-like (HSC-like), demonstrating that such HSC-like cells can achieve three series transplants on animals and have the ability to rebuild multi-lineage long-term hematopoiesis in vivo.

MPP is derived from haematopoietic stem cells (HSCs) that can rapidly differentiate and produce all adult blood lineage cells, and are key progenitor cells for maintaining hematopoietic homeostasis and stress hematopoiesis. Unlike HSCs, MPPs lose the ability to renew themselves, but they have a strong ability to multiply and differentiate, and the number is also large. The problem of the scarcity of HSCs has always been a major obstacle to the clinical treatment of diseases, so inverse differentiation induces MPP to quickly produce new HSCs is a quick shortcut and has been one of the research hotspots in the field of blood regeneration.

Wang Jinyong’s research group has long studied the fate reprogramming and regeneration of hematopoietic lineage, and previous studies have found that Hoxb5 can transdifferentiate ProB cells into T cell lineages in vitro, Runx1 and Hoxa9 can induce pluripotent stem cells to efficiently differentiate into T cell immune lineages, and Lhx2, Hoxa9 and Runx1 can induce pluripotent stem cells to efficiently differentiate into B cell immune lineages. Based on the above work, this study found that genetically engineered expression of foreign Hoxb5 transcription factors in the MPP cell background can induce the production of HSC-like cells in animals, and differentiate to produce the entire adult hematopoietic and immune system.

Wang Jinyong’s group completed this study based on the conditionally expressed Hoxb5 protein gene-edited mouse model Mx1cre/RosaLSL-Hoxb5-EGFP/+ (C57BL/6 background, CD45.2 strain) and wild-type transplant recipient mice (C57BL/6 background, CD45.1 strain). First, wild phenotypic MPP in the bone marrow of a conditionally expressed Hoxb5 gene (CD45.2 strain) was transplanted into wild-type mice in cd45.1 strain, and Hoxb5 expression in MPP was initiated by polycytosine, driving cell fate in bodyweight programming, producing a class of HSC-like cells with a phenotype of CD11b and CD48 surface marker positive (CD11b+CD48+SK), but natural HSCs did not have this phenotype. CD11b+CD48+SK cells have HSC characteristics: they can self-renew like HSCs; they can differentiate into full-lineage adult blood cells; and they can perform serial transplants to achieve long-term hematopoiesis in vivo.

In terms of single-cell transcriptome characteristics, UMAP was used to perform unbiased cluster analysis of four cell populations (natural adult HSCs, natural adult MPP, fetal hepatic HSC and CD11b+CD48+SK cells), and it was found that CD11b+CD48+SK cells maintained the identity imprint of pluripotent hematopoietic progenitor cells, and also possessed some characteristics of hematopoietic stem cells in the fetal hepatic stage, similar to hematopoietic stem cells in the fetal hepatic stage, and were in a state of vigorous proliferation and division. In addition, the study found no evidence that Hoxb5 causes tumorigenesis.

The study provides new ideas for developing alternative sources of traditional bone marrow transplant cells. (Source: China Science Daily, Zhu Hanbin, Huang Bochun)

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