权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mapping human hematopoietic stem cell development

绘制人类造血干细胞发育图谱

基本信息

批准号：
10435434
负责人：
Hanna Katri Annikki Mikkola
金额：
$ 30.42万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10435434
关键词：
Address Adult Anatomy Animal Model Blood Blood Vessels Bone Marrow CD34 gene Cell Lineage Cell Maturation Cell Ontogeny Cell surface Cells Code Communities Conceptus Critical Pathways Data Defect Development EPS15 gene Embryo Endothelium Engraftment Fetal Liver First Pregnancy Trimester Generations Genes Goals Growth Hematological Disease Hematopoiesis Hematopoietic Hematopoietic Stem Cell Specification Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Human Human Biology Human Development In Vitro Knowledge Lead Liver Location MLLT3 gene Maps Medial Molecular Molecular Profiling Monitor Mus Organ Patients Placenta Pluripotent Stem Cells Process Protocols documentation Regenerative Medicine Regulation Reporter Resolution Resources Safety Second Pregnancy Trimester Source Specific qualifier value Stem Cell Development Surface Time TimeLine Tissues Transplantation Umbilical Cord Blood Validation Yolk Sac design fetal hematopoietic stem cell fate hematopoietic stem cell self-renewal hematopoietic tissue hemogenic endothelium human embryonic stem cell human fetus tissue human pluripotent stem cell improved in vivo induced pluripotent stem cell migration molecular marker progenitor programs self-renewal single-cell RNA sequencing stem cell function stem cell therapy stemness tissue stem cells transcription factor transcriptome translational study

项目摘要

SUMMARY Pluripotent stem cells (PSC) are an ideal source for deriving HLA-matched or patient specific hematopoietic stem cells (HSC) for the treatment of blood disorders. However, all the efforts in producing self-renewing hematopoietic stem cells (HSC) from PSC have failed due to our limited understanding of the mechanisms that govern “stemness” in developing human HSC. Although the transcription factors that drive blood specification are relatively well understood, we lack knowledge of the programs that define HSC self-renewal, and why these programs fail in PSC derived hematopoietic cells. Thus, we aim to create a single cell transcriptome map of human HSC ontogeny in vivo and ESC derived cells generated in vitro. The ability to compare human HSC from the critical stages of ontogeny when HSCs are specified (AGM, and possibly the placenta and yolk sac) and expand and mature into fully functional HSC in the conceptus (fetal liver and fetal bone marrow) will allow us to identify pathways that are critical for HSC self-renewal, and that distinguish human HSCs developing in vivo from those that develop in vitro. This analysis will pinpoint key defects that underlie the poor function of ESC derived hematopoietic cells, and offer new solutions for overcoming these molecular barriers. As there is a lack of HSC surface markers that would reliably predict human HSC function, to help monitor the differentiation of properly specified HSCs, we created hESC reporter lines for critical HSC regulatory factors HOXA5, MLLT5 and HLF whose expression is highly enriched in self-renewing human HSCs. We will then compare the in vitro derived candidate HSC to the single cell hemato-vascular lineage map of human hematopoietic tissues as HSCs emerge and expand in vivo. This SHINE-II RO1 is designed to address critical hurdle steps in in vitro HSC generation. These studies can be expanded to mechanistic studies to understand human HSC regulation, and ultimately to translational studies to improve HSC transplantation.

总结