Liver-derived fetal hematopoietic stem cells selectively and preferentially home to the fetal bone marrow

Abstract

In the course of ontogeny, the homing site for the hematopoietic stem cells (HSC) moves with certain predictability from the yolk sac to the liver/spleen and then to the marrow. The pattern of this migration has thus far been established mostly on a morphologic basis. To delineate further the course of this migration and to gain insight into its possible mechanism, we used in utero transplantation of allogeneic or xenogeneic HSC in preimmune sheep fetuses. Sex chromosome, type of hemoglobin, and species-specific surface markers were used to follow the path of transplanted cells in the fetus. Before the development of the bone marrow, transplanted HSC (liver- or marrow-derived) homed exclusively to the liver/spleen. With the development of marrow, around day 60 of gestation (term, 145 days), homing occurred also in the nascent marrow and by day 80 transplanted cells homed exclusively to the marrow. This suggests that there may be a hierarchy in homing sites, with those of the marrow having higher affinity than those of liver/spleen. Interestingly, despite a change in homing that was followed by the expansion of the marrow compartment of HSC (ie, HSC proliferation), these cells did not participate actively in blood cell formation during most of the prenatal period. Liver remained the major hematopoietic organ throughout the gestation. It was only during the perinatal period that this organ assumed the function of hematopoiesis from the liver. This lack of expression of HSC in fetal marrow can possibly be attributable to the immaturity of marrow stroma required for differentiation and maturation of progenitors and the orderly egress of mature cells into the blood stream. The availability of this model allows us to begin studies in the molecular mechanism of stem cell homing in vivo during ontogeny.

Preferential adhesion of fetal liver derived primitive haemopoietic progenitor cells to bone marrow stroma

“…The preferential adhesion of fetal liver HPP-CFC to bone marrow stroma, observed in the present investigation, could be ascribed to the natural migration of fetal liver stem cells to the bone marrow in vivo. This observation is consistent with reports of selective adhesion and homing of sheep fetal liver stem cells to the bone marrow when injected into fetuses between 60 and 80 d of gestation even though the fetal liver was the main site of haemopoiesis at this stage (Zanjani et al, 1993). These authors proposed the existence of a hierarchy of homing sites, in which the bone marrow has the highest affinity for the homing of transplanted haemopoietic stem cells.…”

“…In utero transplantation techniques combined with cell marker studies have enabled investigation of ontogenic haemopoietic cell migration in vivo (Zanjani et al, 1991(Zanjani et al, , 1993Clapp et al, 1995;Hendrikx et al, 1996). Zanjani et al (1993) observed selective adherence of sheep fetal liver cells to bone marrow derived stroma and suggested that a hierarchy of homing sites may exist in which bone marrow has a higher affinity than either fetal liver or spleen. Retrovirally marked rat fetal liver cells have been demonstrated to home to the medullary cavity where they proliferated and gave rise to progenitors in new-born and adult rats (Clapp et al, 1995).…”

Adhesion and homing of blood-borne cells in bone marrow microvessels

“…Homing of circulating blood cells to the BM is a key event not only in BM transplantation, but also for seeding of the BM during fetal development. Studies in sheep and mice have shown that hematopoiesis in the BM occurs only after birth, whereas fetal blood is generated in the yolk sac, fetal liver (FL), and aorta-gonads-mesonephros region [40][41][42]. In the mouse, pluripotent circulating HPC begin to colonize the nascent BM before day 14 of gestation [42].…”

The Biology of Hematopoietic Stem Cells

“…The engraftment of mouse fetuses with fetal liver cells resulted in L TMR throughout adult life (Fleischman et al 1982). Zanjani et al (1993) infused fetal sheep with fetal liver cells and found that the relative representation of the donor cells increased in bone marrow and decreased in the liver with increasing gestational age of the recipient. Although these observations may be indicative of developmentally regulated migration.…”