3213 – multi-modal profiling of human fetal liver hematopoietic stem cells reveals the molecular signature of engraftment

Experimental Hematology(2022)

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摘要
Donor hematopoietic stem cells (HSCs), and more recently a patient's own gene edited HSCs, are at the center of cell-based therapies for a variety of blood disorders. However, the ex vivo culture and manipulation of HSCs required for such therapies poses challenges with respect to retention of engraftment potential. To learn how to better retain or even enhance engraftment capacity of HSCs, we focused on fetal liver (FL) HSCs, as these cells display superior engraftment potential compared to postnatal HSCs. Using CITE-seq, we have profiled 26,407 FL cells at both the transcriptional and protein level. Included in these studies were CD34- cells, CD34+ cells and >7,000 CD34+ GPI-80+ cells, functionally validated to be enriched in engraftment potential. As such, we have achieved unprecedented resolution of engraftable FL HSCs, resulting in a detailed molecular signature of engraftment potential. In addition to factors involved in guarding the balance between quiescence and self-renewal such as ID genes (ID1, ID2, ID3) and NFE2L2, we also identified AHR pathway members and factors linked to aging and the concomitant decline of HSC functionality such as LMNA, distinguishing the most functional HSCs from their less potent downstream progenitors. Moreover, Integration of transcriptomic and cell surface marker expression data predicted that CD201 (EPCR) could be used to specifically enrich for the most functional FL HSCs, which we have validated in subsequent transplantation studies. This comprehensive and multi-modal characterization of engraftment potential to define an essential biological function at a key developmental timepoint serves as a useful resource for the field (https://engraftable-hsc.cells.ucsc.edu) and forms the basis for further biological exploration aimed at identifying conditions that better support HSC functionality ex vivo. Donor hematopoietic stem cells (HSCs), and more recently a patient's own gene edited HSCs, are at the center of cell-based therapies for a variety of blood disorders. However, the ex vivo culture and manipulation of HSCs required for such therapies poses challenges with respect to retention of engraftment potential. To learn how to better retain or even enhance engraftment capacity of HSCs, we focused on fetal liver (FL) HSCs, as these cells display superior engraftment potential compared to postnatal HSCs. Using CITE-seq, we have profiled 26,407 FL cells at both the transcriptional and protein level. Included in these studies were CD34- cells, CD34+ cells and >7,000 CD34+ GPI-80+ cells, functionally validated to be enriched in engraftment potential. As such, we have achieved unprecedented resolution of engraftable FL HSCs, resulting in a detailed molecular signature of engraftment potential. In addition to factors involved in guarding the balance between quiescence and self-renewal such as ID genes (ID1, ID2, ID3) and NFE2L2, we also identified AHR pathway members and factors linked to aging and the concomitant decline of HSC functionality such as LMNA, distinguishing the most functional HSCs from their less potent downstream progenitors. Moreover, Integration of transcriptomic and cell surface marker expression data predicted that CD201 (EPCR) could be used to specifically enrich for the most functional FL HSCs, which we have validated in subsequent transplantation studies. This comprehensive and multi-modal characterization of engraftment potential to define an essential biological function at a key developmental timepoint serves as a useful resource for the field (https://engraftable-hsc.cells.ucsc.edu) and forms the basis for further biological exploration aimed at identifying conditions that better support HSC functionality ex vivo.
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fetal liver,stem cells,engraftment,multi-modal
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