Hematopoiesis and immunity of HOXB4-transduced embryonic stem cell-derived hematopoietic progenitor cells
Hematopoiesis and immunity of HOXB4-transduced embryonic stem cell-derived hematopoietic progenitor cells
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DOI：
10.1182/blood-2007-10-117366
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发表时间：
2008-03-15
期刊：
影响因子：
20.3
通讯作者：
Zavazava, Nicholas
中科院分区：
文献类型：
--
作者：
Chan, Kun-Ming;Bonde, Sabrina;Zavazava, Nicholas
胚胎干细胞从所有3种胚层形成细胞和组织的能力可以被利用来产生可用于治疗疾病的细胞。特别是，与骨髓细胞相比，胚胎干细胞成功生成造血细胞可以提供更安全、免疫原性更低的细胞，骨髓细胞在跨越主要组织相容性复合体屏障时需要严格的宿主预处理。在这里，我们利用异位表达的HOXB4（一种同源盒转录因子）的自我更新特性，生成造血祖细胞（HPCs），成功地诱导了受体小鼠的高水平混合嵌合和长期移植。HPCs部分恢复Rag2(-/-) γ (-/-)(c)免疫缺陷小鼠的脾结构。此外，hpc衍生的新生成的T细胞能够对淋巴细胞性脉络丛脑膜炎病毒产生肽特异性反应，并在CD3刺激下特异性分泌介素-2和干扰素- γ。此外，嵌合小鼠中hpc来源的抗原提呈细胞有效地向野生型T细胞呈递病毒抗原。这些结果首次证明来自异位表达HOXB4的胚胎干细胞的白细胞具有免疫功能，为利用胚胎干细胞衍生的造血干细胞治疗血液和免疫疾病开辟了新的机会。
The ability of embryonic stem (ES) cells to form cells and tissues from all 3 germ layers can be exploited to generate cells that can be used to treat diseases. In particular, successful generation of hematopoietic cells from ES cells could provide safer and less immunogenic cells than bone marrow cells, which require severe host preconditioning when transplanted across major histocompatibility complex barriers. Here, we exploited the self-renewal properties of ectopically ex-pressed HOXB4, a homeobox transcription factor, to generate hematopoietic progenitor cells (HPCs) that successfully induce high-level mixed chimerism and long-term engraftment in recipient mice. The HPCs partially restored splenic architecture in Rag2(-/-)gamma(-/-)(c)-immunodeficient mice. In addition, HPC-derived newly generated T cells were able to mount a peptide-specific response to lymphocytic choriomeningitis virus and specifically secreted interieukin-2 and interferon-gamma upon CD3 stimulation. In addition, HPC-derived antigen presenting cells in chimeric mice efficiently presented viral antigen to wildtype T cells. These results demonstrate for the first time that leukocytes derived from ES cells ectopically expressing HOXB4 are immunologically functional, opening up new opportunities for the use of ES cell-derived HPCs in the treatment of hematologic and immunologic diseases.