The Wave2 scaffold Hem-1 is required for transition of fetal liver hematopoiesis to bone marrow

Abstract

The transition of hematopoiesis from the fetal liver (FL) to the bone marrow (BM) is incompletely characterized. We demonstrate that the Wiskott–Aldrich syndrome verprolin-homologous protein (WAVE) complex 2 is required for this transition, as complex degradation via deletion of its scaffold Hem-1 causes the premature exhaustion of neonatal BM hematopoietic stem cells (HSCs). This exhaustion of BM HSC is due to the failure of BM engraftment of Hem-1−/− FL HSCs, causing early death. The Hem-1−/− FL HSC engraftment defect is not due to the lack of the canonical function of the WAVE2 complex, the regulation of actin polymerization, because FL HSCs from Hem-1−/− mice exhibit no defects in chemotaxis, BM homing, or adhesion. Rather, the failure of Hem-1−/− FL HSC engraftment in the marrow is due to the loss of c-Abl survival signaling from degradation of the WAVE2 complex. However, c-Abl activity is dispensable for the engraftment of adult BM HSCs into the BM. These findings reveal a novel function of the WAVE2 complex and define a mechanism for FL HSC fitness in the embryonic BM niche.

Molecular Modulation of Fetal Liver Hematopoietic Stem Cell Mobilization into Fetal Bone Marrow in Mice

“…However, how intracellular protein in HSCs tailors the transition from the fetal liver into the bone marrow has been limitedly documented. Recently, we investigated the function of Hem1 on fetal hematopoietic stem cell migration [ 82 ] ( Figure 5 ). Hem1 protein is one of the members in the WAVE2 complex, which is composed of the Abi-1, Sra-1, Hem-1, and Wave2 proteins.…”

“…There are comparable numbers of HSCs in both E14.5 Hem1 +/+ and Hem1 −/− fetal livers. However, much less fetal bone marrow HSCs in Hem1 −/− embryos were observed when compared to those in Hem1 +/+ ones [ 82 ]. Consistently, Hem1 −/− fetal liver HSCs failed to rescue lethally γ -ray-irradiated mice.…”

“…These data suggest that Hem1 is required for the transition of HSCs from the fetal liver into the bone marrow. Further studies showed that Hem1 deletion resulted in degradation of the WAVE2 complex with downregulation of Abi-1 and Sra-1 protein, leading to HSC apoptosis [ 82 ]. Deletion of Hem1 does not affect actin polymerization and polarization in fetal liver HSCs but inactivates c-Abl signaling and contributes to an HSC lodging deficiency into the bone marrow niche [ 82 ].…”

“…Further studies showed that Hem1 deletion resulted in degradation of the WAVE2 complex with downregulation of Abi-1 and Sra-1 protein, leading to HSC apoptosis [ 82 ]. Deletion of Hem1 does not affect actin polymerization and polarization in fetal liver HSCs but inactivates c-Abl signaling and contributes to an HSC lodging deficiency into the bone marrow niche [ 82 ]. These findings indicate that application of c-Abl inhibitors to treat diseases, such as leukemia, should be carefully considered during pregnancy.…”

How HSCs Colonize and Expand in the Fetal Niche of the Vertebrate Embryo: An Evolutionary Perspective

“…The cellular processes governing mammalian HSC release from the embryonic niche remain to be fully characterized. However, a recent study has revealed that the FL-to-BM transition required correct formation of the Wiskott–Aldrich syndrome verprolin-homologous (WAVE) protein complex 2, mediated by Hem-1 ( Shao et al, 2018 ). The disruption of this complex leads to a loss of the survival signal c-Abl in FL-HSCs, premature death and reduced BM colonization, highlighting a cell-intrinsic pathway that is required for FL-to-BM transition.…”