[Early ontogeny of the human hematopoietic system]

Immunohistochemistry was used to detect markers of the vascular, stromal and hematopoietic cell compartments in the human embryo and early fetus, from 3 to 15 weeks of gestation. CD34 expression was consistently observed at the surface of vascular endothelial cells from off earliest stages tested, at the single exception of embryonic liver blood vessels. Yolk sac hematopoiesis was very transient and limited to primitive erythropoiesis. Clusters of erythroblasts, monocytes and granulocytes appeared from 4 to 5 weeks of gestation in the liver rudiment. The early development of the bone marrow was marked by the rapid invasion, at 8 weeks, of long bone cartilaginous rudiments by CD68+ osteoclast precursors, CD34+ endothelial cells and by preosteoblasts, leading to the development of large vascular sinuses between ossifying trabeculae. Endogenous erythro- and granulopoiesis developed from week 11 in primary logettes always organized around an arteriole, in a loose stromal mesenchymal network established between the media of these arterioles and the sinusal endothelium. Round, hematopoietic CD34+ cells were seen occasionally in yolk sac blood vessels. In the liver they were rare and intermingled as single cells in the hepatocyte cords; strikingly, CD34+ hematopoietic cells could seldom be detected in the developing bone marrow. In contrast, compact clusters of non-endothelial, round CD34+ CD45+ hematopoietic cells were detected, during the 5th week of development, in close association with the ventral wall of the dorsal aorta. These cells exhibit phenotypic and functional characteristics of very primitive hematopoietic progenitors. This observation is in striking correlation with the evidence accumulated in animal models that stem cells for the late embryonic and adult hematopoietic systems develop inside the embryo per se, in the vicinity of the dorsal aorta. We thus suggest that these aorta-associated CD34+ cells, that exhibit an anatomic localization similar to that of the intraembryonic stem cells identified in the avian and murine embryo, are the real stem of human hematopoiesis.