The relative spatial distribution of in vitro‐CFCs in the bone marrow, responding to specific growth factors

Abstract

Haemopoietic progenitor cells are stimulated by a range of growth factors which promote colony growth in culture. The progenitors are a part of an age-structured developmental hierarchy in the tissue. The growth factors, although overlapping in their effects, stimulate cells preferentially at different stages in this programme. Femoral bone marrow was fractionated into axial (close to the central venous sinus) and marginal (close to the bone surface) cells. Progenitors which responded to IL-3, GM-CSF, G-CSF, M-CSF and SCF were then assayed in soft agar cultures. Consequent plots of their spatial distributions showed that the more primitive cells in vitro (responding to IL-3) were concentrated close to the bone surface. The peak concentrations of cells responding primarily to growth factors with progressively more affinity to more mature progenitor cells correspondingly appeared progressively further from the bone surface and closer to the point of release at the central venous sinus. This suggests that the developmental/maturational process in haemopoiesis is accompanied by a progressive movement of cells from the bone surface towards the central axial regions of the bone cavities. The most primitive cells are however exposed, close to the centre of the cavity, by a combination of SCF and G-CSF (or by a 50-fold increase in G-CSF concentration alone). These results corroborate earlier data which indicate a developmental movement of cells from the centre of the marrow tissue towards the bone surface and back again, sequentially encountering a series of growth factors which promote their differentiation into mature cells, for release at the central venous sinus.

Spatial Distribution of Blood Vessels and CD34+ Hematopoietic Stem and Progenitor Cells Within the Marrow Cavities of Human Cancellous Bone

“…Animal studies, however, support the hypothesis that the hematopoietic stem cells and progenitor cells are localized much closer to the bone trabecula surfaces and decrease in concentration within deeper regions of bone marrow (12,13). Work by Frassoni et al (14), Lord (15), and Cui et al (16) on the mouse femoral shaft have demonstrated a clear spatial gradient in the distribution of different cell lines responding to marrow growth factors as a function of distance into the femoral medullary cavity. The presence of a spatial gradient in hematopoietic stem and progenitor cells within human bone marrow could possibly be significant in the construction of dose-response models for marrow toxicity in cases in which the marrow absorbed dose itself is delivered nonuniformly.…”

“…Although larger fields of view and 3D image analyses should be pursued to further validate the distributions shown here, it is clear that the spatial gradients seen in the mouse femur study of Cui et al (16) are also present in human bone marrow. In the mouse femur, colony-forming cells responding to IL-3 demonstrated an approximately lognormal concentration gradient with distance away from the corticomedullary interface moving toward the femoral central artery.…”

Osteoblastic cells regulate the haematopoietic stem cell niche

“…The recent finding that Hh pathway activity is important for growth of a significant proportion of small-cell lung cancers 7 , a tumour type not associated with Gorlin's syndrome, suggested that other, non-Gorlin's tumours might require Hh pathway activity for growth. We investigate here the role of pathway activity in tumours derived from the gut, a tissue with prominent and diverse roles for Hh signalling in developmental patterning, and in mature tissue homeostasis.…”

“…Therefore, osteoblastic cells are a regulatory component of the haematopoietic stem cell niche in vivo that influences stem cell function through Notch activation. Niche constituent cells or signalling pathways provide pharmacological targets with therapeutic potential for stem-cell-based therapies.Mammalian bone marrow architecture involves haematopoietic stem cells (HSCs) in close proximity to the endosteal surfaces 5,6 , with more differentiated cells arranged in a loosely graduated fashion as the central longitudinal axis of the bone is approached 5,7,8 . This nonrandom organization of the marrow suggests a possible relationship between HSCs and osteoblasts-osteogenic cells lining the endosteal surface.…”

“…Mammalian bone marrow architecture involves haematopoietic stem cells (HSCs) in close proximity to the endosteal surfaces 5,6 , with more differentiated cells arranged in a loosely graduated fashion as the central longitudinal axis of the bone is approached 5,7,8 . This nonrandom organization of the marrow suggests a possible relationship between HSCs and osteoblasts-osteogenic cells lining the endosteal surface.…”