Early ontogenic origin of the hematopoietic stem cell lineage

Abstract

Several lines of evidence suggest that the adult hematopoietic system has multiple developmental origins, but the ontogenic relationship between nascent hematopoietic populations under this scheme is poorly understood. In an alternative theory, the earliest definitive blood precursors arise from a single anatomical location, which constitutes the cellular source for subsequent hematopoietic populations. To deconvolute hematopoietic ontogeny, we designed an embryo-rescue system in which the key hematopoietic factor Runx1 is reactivated in Runx1-null conceptuses at specific developmental stages. Using complementary in vivo and ex vivo approaches, we provide evidence that definitive hematopoiesis and adult-type hematopoietic stem cells originate predominantly in the nascent extraembryonic mesoderm. Our data also suggest that other anatomical sites that have been proposed to be sources of the definitive hematopoietic hierarchy are unlikely to play a substantial role in de novo blood generation.

The human chorion contains definitive hematopoietic stem cells from the fifteenth week of gestation

“…This finding is in line with data from timed rescue of Runx1 null mouse embryos, which showed that definitive, adult-type HSCs originate in the nascent extraembryonic mesoderm before the fetal liver initiates definitive hematopoiesis (Tanaka et al, 2012).…”

Distinct temporal requirements for Runx1 in hematopoietic progenitors and stem cells

“…Tanaka et al (Tanaka et al, 2012) previously showed that restoration of Runx1 expression from the endogenous Runx1 locus at E6.5 and E7.5 could rescue EMP formation and viability of Runx1-deficient embryos, whereas restoring Runx1 expression at E8.0 or later could not. Their experimental design utilized Cre ERT expressed from one endogenous Runx1 allele to permanently restore Runx1 expression from the other, conditionally activated Runx1 allele.…”

“…The end of the requirement is likely to reflect the termination of a three-day process of EMP formation from endothelium. Tanaka et al also defined the beginning of the Runx1 requirement for HSC formation as E7.5 (Tanaka et al, 2012). Although they showed by transplantation experiments that HSCs were rescued when Runx1 was reactivated at E7.5, they did not directly assess HSC function by transplantation upon reactivation at later time points, and instead used fetal viability and CFU-C activity in the AGM region as surrogates for HSC rescue.…”

“…Their experimental design utilized Cre ERT expressed from one endogenous Runx1 allele to permanently restore Runx1 expression from the other, conditionally activated Runx1 allele. The Tanaka et al (Tanaka et al, 2012) study defines the beginning of the Runx1 requirement for EMP formation as E7.5, and we have defined the end of the requirement as E10.5. The end of the requirement is likely to reflect the termination of a three-day process of EMP formation from endothelium.…”

Lymphoid Progenitor Emergence in the Murine Embryo and Yolk Sac Precedes Stem Cell Detection

“…This observation implied that some of the endothelial cells in these HSC-producing regions were derived from E7.5-labeled yolk sac cells. In a subsequent study, Tanaka et al developed an inducible Runx1 rescue system by a single tamoxifen injection in Runx1 knockout embryos [132]. Definitive hematopoiesis and HSC generation were rescued by a single injection of tamoxifen at E6.5 to E7.5, but not at any other time point [132].…”