Kitajima Kenji, Takahashi Yuna, Ando Hikaru, Shingai Minako, Hamasaki Mako, Tanikawa Miyu, Kanokoda Mai, Nakajima Marino, Nishito Yasumasa, Hara Takahiko
Stem Cell Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
Front Cell Dev Biol. 2024 Oct 15;12:1482989. doi: 10.3389/fcell.2024.1482989. eCollection 2024.
Hematopoietic stem cells (HSCs) obtained from patient-derived human induced pluripotent stem cells (iPSCs) are a promising tool for curing various hematological disorders. We previously demonstrated that enforced expression of the LIM-homeobox transcription factor Lhx2, which is essential for mouse embryonic hematopoiesis, leads to generation of engraftable and expandable hematopoietic stem cells (HSCs) from mouse iPSCs. However, it remained unknown whether Lhx2 can induce HSCs from human iPSCs. Here, we investigated the effect of Lhx2 overexpression on hematopoietic differentiation of human iPSCs. Unexpectedly, Lhx2 severely inhibited proliferation of human iPSC-derived hematopoietic cells. Thus, Lhx2 exhibited differential effects on mouse and human hematopoietic cells. Further studies implied that the inhibitory effect of Lhx2 on human iPSC-derived hematopoietic cells was due to insufficient transcriptional activation ability. Therefore, we modified Lhx2 to strengthen its activity as a transcriptional activator. This modified Lhx2 could induce amplification of human iPSC-derived hematopoietic stem/progenitor cells (HSPCs). We believe that these findings will facilitate the development of a method to efficiently produce HSCs from human iPSCs.
从患者来源的人诱导多能干细胞（iPSC）中获得的造血干细胞（HSC）是治疗各种血液疾病的一种有前景的工具。我们之前证明，对小鼠胚胎造血至关重要的LIM同源框转录因子Lhx2的强制表达，可从小鼠iPSC中产生可移植和可扩增的造血干细胞（HSC）。然而，Lhx2是否能从人iPSC中诱导产生HSC仍不清楚。在此，我们研究了Lhx2过表达对人iPSC造血分化的影响。出乎意料的是，Lhx2严重抑制了人iPSC来源的造血细胞的增殖。因此，Lhx2对小鼠和人造血细胞表现出不同的作用。进一步的研究表明，Lhx2对人iPSC来源的造血细胞的抑制作用是由于转录激活能力不足。因此，我们对Lhx2进行了修饰，以增强其作为转录激活因子的活性。这种修饰后的Lhx2可诱导人iPSC来源的造血干/祖细胞（HSPC）的扩增。我们相信，这些发现将有助于开发一种从人iPSC高效生产HSC的方法。
