Liang Guixian, Liu Shicheng, Zhou Chunyu, Liu Mengyao, Zhang Yifan, Ma Dongyuan, Wang Lu, Han Jing-Dong J, Liu Feng
Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
Cell Discov. 2025 Jan 28;11(1):9. doi: 10.1038/s41421-024-00760-2.
Hematopoietic stem and progenitor cells (HSPCs) are critical for the treatment of blood diseases in clinic. However, the limited source of HSPCs severely hinders their clinical application. In the embryo, hematopoietic stem cells (HSCs) arise from hemogenic endothelial (HE) cells lining the major arteries in vivo. In this work, by engineering vascular niche endothelial cells (VN-ECs), we generated functional HSPCs in vitro from ECs at various sites, including the aorta-gonad-mesonephros (AGM) region and the placenta. Firstly, we converted mouse embryonic HE cells from the AGM region (aHE) into induced HSPCs (iHSPCs), which have the abilities for multilineage differentiation and self-renewal. Mechanistically, we found that VN-ECs can promote the generation of iHSPCs via secretion of CX3CL1 and IL1A. Next, through VN-EC co-culture, we showed that placental HE (pHE) cells, a type of extra-embryonic HE cells, were successfully converted into iHSPCs (pHE-iHSPCs), which have multilineage differentiation capacity, but exhibit limited self-renewal ability. Furthermore, comparative transcriptome analysis of aHE-iHSPCs and pHE-iHSPCs showed that aHE-iHSPCs highly expressed HSC-specific and self-renewal-related genes. Moreover, experimental validation showed that retinoic acid (RA) treatment promoted the transformation of pHE cells into iHSPCs that have self-renewal ability. Collectively, our results suggested that pHE cells possess the potential to transform into self-renewing iHSPCs through RA treatment, which will facilitate the clinical application of placental endothelial cells in hematopoietic cell generation.
造血干细胞和祖细胞（HSPCs）在临床上对血液疾病的治疗至关重要。然而，HSPCs来源有限严重阻碍了它们的临床应用。在胚胎中，造血干细胞（HSCs）起源于体内主要动脉内衬的造血内皮（HE）细胞。在这项研究中，通过工程化血管龛内皮细胞（VN-ECs），我们在体外从包括主动脉-性腺-中肾（AGM）区域和胎盘在内的各个部位的内皮细胞中生成了功能性HSPCs。首先，我们将来自AGM区域的小鼠胚胎HE细胞（aHE）转化为具有多谱系分化和自我更新能力的诱导HSPCs（iHSPCs）。从机制上讲，我们发现VN-ECs可以通过分泌CX3CL1和IL1A促进iHSPCs的生成。接下来，通过与VN-EC共培养，我们表明胎盘HE（pHE）细胞，一种胚外HE细胞，成功转化为具有多谱系分化能力但自我更新能力有限的iHSPCs（pHE-iHSPCs）。此外，对aHE-iHSPCs和pHE-iHSPCs的比较转录组分析表明，aHE-iHSPCs高度表达HSC特异性和自我更新相关基因。此外，实验验证表明，视黄酸（RA）处理促进了pHE细胞向具有自我更新能力的iHSPCs的转化。总的来说，我们的结果表明，pHE细胞具有通过RA处理转化为自我更新的iHSPCs的潜力，这将促进胎盘内皮细胞在造血细胞生成中的临床应用。
