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

Abstract

Current bone marrow dosimetry methods inherently assume that the target cells of interest for the assessment of leukemia risk (stochastic effects) or marrow toxicity (deterministic effects) are uniformly localized throughout the marrow cavities of cancellous bone. Previous studies on mouse femur, however, have demonstrated a spatial gradient for the hematopoietic stem and progenitor cells, with higher concentrations near the bone surfaces. The objective of the present study was to directly measure the spatial concentration of these cells, as well as marrow vasculature structures, within images of human disease-free bone marrow. Methods: Core-biopsy samples of normal bone marrow from the iliac crest were obtained from clinical cases at Shands Hospital at the University of Florida Department of Pathology. The specimens were sectioned and immunohistochemically stained for CD34 (red) and CD31 (brown) antigens. These 2 stains were used simultaneously to differentiate between hematopoietic stem and progenitor cells (CD34 1 /CD31 2 ) and vascular endothelium (CD34 1 /CD31 1 ). Distances from hematopoietic CD34 1 cells and blood vessels to the nearest bone trabecula surface were measured digitally and then binned in 50-mm increments, with the results then normalized per unit area of marrow tissue. The distances separating hematopoietic CD34 1 cells from vessels were also tallied. Results: Hematopoietic CD34 1 cells were found to exist along a linear spatial gradient with a maximal areal concentration localized within the first 50 mm of the bone surfaces. An exponential spatial concentration gradient was found in the concentration of blood vessel fragments within the images. Distances between hematopoietic CD34 1 cells and blood vessels exhibited a lognormal distribution indicating a shared spatial niche. Conclusion: Study results confirm that the spatial gradient of hematopoietic stem and progenitor cells previously measured in mouse femur is also present within human cancellous bone. The dosimetric implication of these results may be significant for those scenarios in which the absorbed dose itself is nonuniformly delivered across the marrow tissues, as would be the case for a low-energy b-or a-particle emitter localized on the bone surfaces.

Extension of the biological effective dose to the MIRD schema and possible implications in radionuclide therapy dosimetry

“…It should be noted that the bone marrow is a highly complex organ and other factors that may influence dose response, such as spatial distribution of active bone marrow and hematopoietic cells, remain outside the scope of the present study. 31 In the case of kidneys, the RE factors take higher values than in the case of red marrow. For effective clearance half-times between 10 and 60 h, the RE to the renal cortex ranges between 1.5 and 4.…”

Toward Patient-Friendly Cell-Level Dosimetry

“…The paper in this issue of The Journal of Nuclear Medicine by Watchman et al (25) adds to this group's already impressive contributions to this area. The article provides the basic data and describes a formalism for taking a step toward cell-level dosimetry while remaining within the overall MIRD S value formalism.…”

Spatial gradients of blood vessels and hematopoietic stem and progenitor cells within the marrow cavities of the human skeleton

“…[1][2][3] Although several groups have investigated the spatial location of hematopoietic stem and progenitor cells (HSPCs) in murine models, [4][5][6][7] evidence for corresponding HSPC spatial profiles within human bone marrow has only recently been established. 8 In their study, Watchman et al used novel methods for the digital quantification of the CD34 ϩ hematopoietic stem cells and blood vessel fragments (BVFs) in human iliac crest. 8 The present study uses similar techniques of immunohistochemistry and digital image processing to directly measure the concentration of BVFs and CD34 ϩ HSPCs as a function of distance from the most proximal trabecular surface in human bone marrow.…”

“…8 In their study, Watchman et al used novel methods for the digital quantification of the CD34 ϩ hematopoietic stem cells and blood vessel fragments (BVFs) in human iliac crest. 8 The present study uses similar techniques of immunohistochemistry and digital image processing to directly measure the concentration of BVFs and CD34 ϩ HSPCs as a function of distance from the most proximal trabecular surface in human bone marrow. The study further advances the findings of Watchman et al, however, through (1) immunohistochemical stratification of the additional population of CD117 ϩ hematopoietic stem and progenitor cells, (2) consideration of a possible bone-site dependence of the BVF and HSPC spatial gradient, (3) use of larger field-of-view marrow specimens through autopsy harvest, and (4) explicit consideration of active versus total bone marrow area.…”