ENGRAFTMENT OF HUMAN HEMATOPOIETIC PRECURSOR CELLS WITH SECONDARY TRANSFER POTENTIAL IN SCID-HU MICE
ENGRAFTMENT OF HUMAN HEMATOPOIETIC PRECURSOR CELLS WITH SECONDARY TRANSFER POTENTIAL IN SCID-HU MICE
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DOI：
10.1182/blood.v84.8.2497.bloodjournal8482497
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发表时间：
1994-10-15
期刊：
影响因子：
20.3
通讯作者：
CHEN, SC
中科院分区：
文献类型：
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作者：
CHEN, BP;GALY, A;CHEN, SC
将人类胎儿骨碎片皮下植入免疫缺陷（SCID）小鼠体内，维持活跃的人类造血功能。在这项研究中，我们表明这种人类造血微环境支持从胎儿和成人骨髓（BM）中分离出的HLA不匹配的CD34（+）原始造血祖细胞的植入和分化。 BM CD34(+)细胞的CD2、CD14、CD15、CD16被耗尽。血型糖蛋白 A 和 CD19 谱系定型细胞 (CD34(+)Lin(-))。供体细胞植入表现为供体 HLA 表型的 B (CD19(+)) 和骨髓 (CD33(+)) 细胞的存在。胎儿骨髓供体细胞注射后 4 周即可观察到成功植入，并持续至少 12 周，第 8 周和第 12 周时的植入成功率分别为 100%（11/11 移植物）和 92%（11/12 移植物）。在成功移植 HLA 不匹配的 CD34(+)Lin(-) 供体细胞的 SCID-hu 骨中，一致观察到供体和内源细胞的混合 BM 嵌合现象。在细胞注射前立即用单剂量亚致死（350拉德）全身照射（WBI）对SCID-hu骨进行预处理，增强了供体细胞在骨移植物上的再增殖，并且在某些情况下，导致完全再增殖。 WBI后，仅将500个胎儿骨髓CD34(+)Lin(-)细胞注射到人骨移植物中，就产生了供体来源的造血。注射后 8 周从 SCID-hu 骨移植物中回收的供体祖细胞能够在 SCID-hu 小鼠中重新填充 HLA 不同的胎儿人类骨骼的第二组，并在一些受者中使用 B 细胞和骨髓细胞以及 CD34(+) 细胞。此外，这些细胞在 SCID 小鼠的胎儿胸腺片段中重新填充了供体胸腺细胞，包括未成熟的 CD4(+)CD8(+) 和成熟的 CD4(+)CD8(-) 以及 CD4(-)CD8(+) 亚群。这些结果表明，SCID-hu 小鼠的胎儿人骨植入物可以支持维持具有多谱系潜力和再增殖潜力的细胞群长达 16 周。 SCID-hu 骨模型始终支持胎儿和成人 CD34(+)Lin(-) 细胞的植入，而无需向这些动物施用外源人细胞因子。该模型目前用于分离和表征候选人类造血干细胞 (HSC)，并为人类 HSC 治疗提供重要信息。 (C) 1994 年，美国血液学会。
Human fetal bone fragments implanted subcutaneously in immunodeficient (SCID) mice maintain active human hematopoiesis. In this study, we show that this human hematopoietic microenvironment supports the engraftment and differentiation of HLA-mismatched, CD34(+) primitive hematopoietic progenitor cells isolated from fetal and adult human bone marrow (BM). The BM CD34(+) cells were depleted of CD2, CD14, CD15, CD16. glycophorin A, and CD19 lineage-committed cells (CD34(+)Lin(-)). Donor cell engraftment was manifested by the presence of B (CD19(+)) and myeloid (CD33(+)) cells of donor HLA phenotype. Successful engraftment was observed as early as 4 weeks after fetal BM donor cell injection and sustained for at least 12 weeks, with engraftment success rates of 100% (11/11 grafts) and 92% (11/12 grafts) at 8 and 12 weeks, respectively. Mixed BM chimerism of donor and endogenous cells was consistently observed in SCID-hu bones successfully engrafted with HLA-mismatched CD34(+)Lin(-) donor cells. Preconditioning of the SCID-hu bone with a single dose of sublethal (350 rad) whole body irradiation (WBI) immediately before cell injection enhanced the repopulation of the bone grafts with donor cells and, in some instances, resulted in complete repopulation. After WBI, as few as 500 fetal bone marrow CD34(+)Lin(-) cells injected in the human bone grafts resulted in donor-derived hematopoiesis. Donor progenitor cells recovered from the SCID-hu bone grafts 8 weeks postinjection had the capacity to repopulate secondary groups of HLA-disparate fetal human bones in SCID-hu mice with B and myeloid cells as well as CD34(+) cells in some recipients. In addition, these cells repopulated fetal human thymus fragments in SCID mice with donor thymocytes including immature CD4(+)CD8(+) and mature CD4(+)CD8(-) as well as CD4(-)CD8(+) subsets. These results indicate that the fetal human bone implants of SCID-hu mice can support the maintenance of a cell population that has both multilineage potential and repopulating potential for periods of time as long as 16 weeks. The SCID-hu bone model consistently supported the engraftment of both fetal and adult CD34(+)Lin(-) cells without the administration of exogenous human cytokines to these animals. This model is currently being used to permit the isolation and characterization of candidate human hematopoietic stem cells (HSCs) and provide important information critical for human HSC therapy in humans. (C) 1994 by The American Society of Hematology.