Uniparental cells:Hematopoietic reconstitution potential

单亲细胞：造血重建潜力

• 批准号: 6702737
• 负责人: Kenneth J McLaughlin
• 金额: $ 7.93万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6702737
• 关键词: cell biology; cell differentiation; cell morphology; cell population study; diploidy; embryo /fetus; embryonic stem cell; fertilization; genomic imprinting; hematopoiesis; hematopoietic stem cells; laboratory mouse; liver; mature animal; pluripotent stem cells; stem cell transplantation; tissue mosaicism

DESCRIPTION (provided by applicant): Human embryonic stem cells have promising potential for therapeutic use. However, as they are derived by disaggregation of potentially viable human embryos their production and use has serious ethical as well as legal complications. A less controversial alternative could be the use of uniparental embryos with duplicate maternal or paternal genomes that are not viable on their own, but can still form pluripotent ES cells. Uniparental cells can contribute to many adult tissues when combined with normal embryos to form chimeras. It is unclear, however, if this is an advantageous consequence of co-development with fertilized cells, or if uniparental cells can cell-autonomously form certain cell types, including stem cells. It is also not known whether embryonic or fetal cells of uniparental origin will repopulate after being grafted directly into adult tissues, a prerequisite for therapeutic applications. As a functional model to test engraftment of uniparental cells, the investigators will perform hematopoietic reconstitution of adult recipients with uniparental fetal liver cells. Preliminary findings indicate that uniparental cells contribute substantially to the fetal livers of chimeras, including primitive hematopoietic cells. The investigators will characterize uniparental cell contribution to fetal liver hematopoietic stem cells using morphological as well as functional characteristics. Contribution of uniparental cells to stem cell enriched populations of fetal liver will be assessed using cell surface markers. Functionality of uniparental cells will be tested by transplantation of uniparental chimeric as well as enriched uniparental fetal liver cells to irradiated adult recipients and analysis of uniparental contribution to the hematopoietic system of reconstituted recipients. Short- and long-term repopulation as well as the contribution to hematopoietic lineages will be observed. The competitive transplantation experiments will furthermore assess the ability of uniparental cells to compete with fertilized cells. This application will be the first test of the functional potential of uniparental cells transplanted into adults, while simultaneously providing novel information about the consequences of genomic imprinting for stem cell function in both fetal development and in the adult. The results will also provide the basis for two future applications being (1) the role on imprinting in hematopoiesis, and (2) the broader use of uniparental cells for therapeutic application.

描述（由申请人提供）：人胚胎干细胞具有良好的治疗潜力。 然而，由于它们是通过分解可能存活的人类胚胎而获得的，因此它们的生产和使用具有严重的伦理和法律的复杂性。 一个争议较小的替代方案可能是使用具有重复的母系或父系基因组的单亲胚胎，这些胚胎本身不能存活，但仍然可以形成多能ES细胞。 当与正常胚胎结合形成嵌合体时，单亲细胞可以贡献于许多成年组织。 然而，目前还不清楚这是否是与受精细胞共同发育的有利结果，或者单亲细胞是否可以自主形成某些细胞类型，包括干细胞。 也不知道单亲来源的胚胎或胎儿细胞在直接移植到成人组织后是否会重新繁殖，这是治疗应用的先决条件。 作为测试单系细胞植入的功能模型，研究者将用单系胎肝细胞对成人受体进行造血重建。 初步研究结果表明，单亲细胞的嵌合体，包括原始造血细胞的胎儿肝脏作出重大贡献。 研究者将使用形态学和功能特征来表征单亲细胞对胎肝造血干细胞的贡献。 将使用细胞表面标志物评估单系细胞对胎肝干细胞富集群体的贡献。 将通过将单亲嵌合以及富集的单亲胎肝细胞移植至经辐照的成人受体并分析单亲对重建受体的造血系统的贡献来测试单亲细胞的功能。 将观察短期和长期再增殖以及对造血谱系的贡献。 竞争性移植实验将进一步评估单亲细胞与受精细胞竞争的能力。 这项应用将是移植到成人的单亲细胞的功能潜力的第一个测试，同时提供新的信息的后果基因组印记的干细胞功能在胎儿发育和成人。 这些结果也将为两个未来的应用提供基础，即（1）印迹在造血中的作用，和（2）更广泛地使用单亲细胞进行治疗应用。