Uniparental cells:Hematopoietic reconstitution potential

单亲细胞：造血重建潜力

• 批准号: 6830294
• 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 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6830294
• 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）：人类胚胎干细胞具有良好的治疗用途潜力。 然而，由于它们是通过分解潜在可行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复杂性。 一种争议较小的替代方案可能是使用具有重复母本或父本基因组的单亲胚胎，这些胚胎本身无法存活，但仍可以形成多能 ES 细胞。 当单亲细胞与正常胚胎结合形成嵌合体时，可以形成许多成体组织。 然而，尚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细胞自主地形成某些细胞类型，包括干细胞。 目前还不清楚单亲来源的胚胎或胎儿细胞在直接移植到成体组织中后是否会重新增殖，这是治疗应用的先决条件。 作为测试单亲细胞植入的功能模型，研究人员将用单亲胎儿肝细胞对成年受体进行造血重建。 初步研究结果表明，单亲细胞对嵌合体的胎儿肝脏有很大贡献，包括原始造血细胞。 研究人员将利用形态和功能特征来表征单亲细胞对胎儿肝脏造血干细胞的贡献。 将使用细胞表面标记物评估单亲细胞对富含干细胞的胎儿肝脏群体的贡献。 将通过将单亲嵌合体以及富集的单亲胎儿肝细胞移植到受辐射的成年受体中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。 将观察短期和长期的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。 该应用将首次测试移植到成人体内的单亲细胞的功能潜力，同时提供有关基因组印记对胎儿发育和成人干细胞功能的影响的新信息。 该结果还将为未来的两个应用提供基础：（1）印记在造血过程中的作用，以及（2）单亲细胞在治疗应用中的更广泛应用。

项目成果

Mouse Parthenogenetic Embryonic Stem Cells with Biparental-Like Expression of Imprinted Genes Generate Cortical-Like Neurons That Integrate into the Injured Adult Cerebral Cortex.

具有印迹基因的二胎样表达的小鼠孤态发生的胚胎干细胞会产生类似皮质的神经元，这些神经元整合到受伤的成年大脑皮层中。

• DOI: 10.1002/stem.2721
• 发表时间: 2018-03
• 期刊: Stem cells (Dayton, Ohio)
• 作者: Varrault A;Eckardt S;Girard B;Le Digarcher A;Sassetti I;Meusnier C;Ripoll C;Badalyan A;Bertaso F;McLaughlin KJ;Journot L;Bouschet T
• 通讯作者: Bouschet T

In vivo and in vitro differentiation of uniparental embryonic stem cells into hematopoietic and neural cell types.

单亲胚胎干细胞在体内和体外分化为造血细胞和神经细胞类型。

• DOI: 10.4161/org.6123
• 发表时间: 2008
• 期刊: Organogenesis
• 影响因子: 2.3
• 作者: Eckardt,Sigrid;Dinger,TimoC;Kurosaka,Satoshi;Leu,NAdrian;Müller,AlbrechtM;McLaughlin,KJohn
• 通讯作者: McLaughlin,KJohn