Recombinant IL-7/HGFβ efficiently induces transplantable murine hematopoietic stem cells
Recombinant IL-7/HGFβ efficiently induces transplantable murine hematopoietic stem cells
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DOI：
10.1172/jci46055
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发表时间：
2012-10-01
影响因子：
15.9
通讯作者：
Goldschneider, Irving
中科院分区：
文献类型：
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作者：
Lai, Laijun;Zhang, Mingfeng;Goldschneider, Irving
直接从供者获得足够的造血干细胞(HSCs)的困难限制了HSC移植的临床应用。许多用细胞因子和生长因子刺激纯化的HSC体外生长的尝试通常只引起HSC数量的轻微增加，而降低了它们在体内的重建能力。我们之前开发了一种重组单链形式的自然产生的小鼠杂交细胞因子IL-7和肝细胞生长因子β链(rIL-7/HGFβ)，可刺激小鼠骨髓培养中常见的淋巴祖细胞、前B细胞和造血祖细胞(第12天脾克隆形成单位)的体外增殖和/或分化。在这里，我们使用rIL-7/HGFβ在培养中诱导来自多种细胞来源的大量HSCs，包括未分离的BM细胞、纯化的HSCs、CD45(-)BM细胞和胚胎干细胞。在每种情况下，大多数HSCs都处于细胞周期的G(0)期，表现出氧化应激减少，凋亡减少，CXCR4表达增加。此外，当静脉注射时，这些HSCs迁移到BM，自我复制，提供辐射防护，并建立长期的造血重建。通过将rIL-7/HGFβ直接注射到骨髓腔内而不是通过rIL-7、rHGF和/或rHGFβ处理，这些特性被放大。
Difficulty obtaining sufficient hematopoietic stem cells (HSCs) directly from the donor has limited the clinical use of HSC transplantation. Numerous attempts to stimulate the ex vivo growth of purified HSCs with cytokines and growth factors generally have induced only modest increases in HSC numbers while decreasing their in vivo reconstituting ability. We previously developed a recombinant single-chain form of a naturally occurring murine hybrid cytokine of IL-7 and the beta chain of hepatocyte growth factor (rIL-7/HGF beta) that stimulates the in vitro proliferation and/or differentiation of common lymphoid progenitors, pre-pro-B cells, and hematopoietic progenitor cells (day 12 spleen colony-forming units) in cultures of mouse BM. Here we used the rIL-7/HGF beta in culture to induce large numbers of HSCs from multiple cell sources, including unseparated BM cells, purified HSCs, CD45(-) BM cells, and embryonic stem cells. In each instance, most of the HSCs were in the G(0) phase of the cell cycle and exhibited reduced oxidative stress, decreased apoptosis, and increased CXCR4 expression. Furthermore, when injected i.v., these HSCs migrated to BM, self-replicated, provided radioprotection, and established long-term hematopoietic reconstitution. These properties were amplified by injection of rIL-7/HGF beta directly into the BM cavity but not by treatment with rIL-7, rHGF, and/or rHGF beta.