Abstract
A hypomorphic Prep1 mutation results in embryonic lethality at late gestation with a pleiotropic embryonic phenotype that includes defects in all hematopoietic lineages. Reduced functionality of the hematopoietic stem cells (HSCs) compartment might be responsible for the hematopoietic phenotype observed at mid-gestation. In this paper we demonstrate that Prep1 regulates the number of HSCs in fetal livers (FLs), their clonogenic potential and their ability to de novo generate the hematopoietic system in ablated hosts. Furthermore, we show that Prep1 controls the self-renewal ability of the FL HSC compartment as demonstrated by serial transplantation experiments. The premature exhaustion of Prep1 mutant HSCs correlates with the reduced quiescent stem cell pool thus suggesting that Prep1 regulates the self-renewal ability by controlling the quiescence/proliferation balance. Finally, we show that in FL HSCs Prep1 absence induces the interferon signaling pathway leading to premature cycling and exhaustion of fetal HSCs.
Highlights
Hematopoiesis is the production of blood cells in the embryo and throughout adult life
We demonstrate that Prep1 regulates the number of Hematopoietic stem cells (HSCs) in fetal livers (FLs) as well as their functionality to de novo generate the hematopoietic system in ablated hosts
Since Sca-1 is an IFNinducible gene [35] and is upregulated by IFNs in FL HSCs [33], we investigated whether other components of this signaling pathway are perturbed in Prep1i/i HSCs measuring the mRNA level of a panel of genes implicated in the IFN response (Figure 6C)
Summary
Hematopoiesis is the production of blood cells in the embryo and throughout adult life. At mid-late gestation in FL, HSCs undergo a massive expansion generating the stem cell pool that will contribute to mature blood cells during entire life. Around birth HSCs move to the bone marrow (BM) where they reside mainly in a quiescent state during adult life [2]. Intrinsic factors, such as transcription factors and chromatin modifiers, and extrinsic microenvironmental factors encircling the HSCs modulate their activity during both embryonic and adult life [3]. Identifying the mechanisms regulating HSCs during development is crucial since often cells undergoing malignant transformation reacquire properties distinctive of stem cells during developmental stages [10,11,12,13,14]. Factors regulating expansion and proliferation of FL HSCs might help developing protocols for ex vivo expansion of HSCs for clinical applications
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