CD34+/CD105+ cells are enriched in primitive circulating progenitors residing in the G0 phase of the cell cycle and contain all bone marrow and cord blood CD34+/CD38^low/− precursors

Abstract

Summary. A subset of circulating CD34 cells was found to express CD105 antigen. Sorting experiments showed that most granulocyte±macrophage colony-forming units (GM-CFU) and burst-forming units ± erythroid (BFU-E) were retained in the CD34/CD105À fraction, whereas rare GM-CFU/BFU-E were generated from CD34/CD105 cells. Megakaryocytic aggregates were entirely retained in the CD34/CD105 fraction. Neutralizing doses of an anti-TGF-b1 antibody demonstrated CD34/CD105 cells capable of colony-forming activity without any signi®cant effect on CD34/CD105À cells. Cloning of secondary colonies revealed that CD34/CD105 cells had a signi®cantly higher secondary cloning ef®ciency than CD34/CD105À cells. CD34/CD105 cells had a signi®cantly higher long-term culture-initiating cell (LTC-IC) frequency than CD34/CD105À cells. Kinetic analysis showed that 75% of CD34/CD105 cells consisted of DNA 2n G0Ki-67À cells whereas 82% of CD34/CD105À were DNA 2n G1Ki-67 cells, and this latter subset showed a RNA content consistently higher than CD34/CD105 cells. CD34/ CD105 progenitors were CD25, whereas CD34/ CD105À contained a small CD25 subset. Three-colour analysis of bone marrow and cord blood CD34 cells demonstrated that all the CD34/CD38 low/À primitive precursors were contained in CD34/CD105 cells. Extensive characterization of these CD105 precursors indicated that they have biological properties associated with primitive haematopoietic precursors.

Expression and function of CD105 during the onset of hematopoiesis from Flk1+ precursors

“…56,58,59 For example, TGF-␤1 was shown to inhibit the expression of stem cell factor and its receptor CD117 (c-kit) 60 and was also shown to be a major regulator of erythropoiesis, inhibiting early stages but stimulating later stages. 58 Interestingly, Pierelli et al 40 reported that CD105 is expressed on primitive HSCs and suggested that autocrine TGF-␤1 helps to maintain the resting state and self-renewal capacity of these cells. Other members of the TGF-␤ superfamily, such as activin-A, BMP-2, BMP-4, and BMP-7, have also been implicated as important regulators of mesodermal specification to the hematopoietic fate, or of early hematopoietic differentiation.…”

Complex and Context Dependent Regulation of Hematopoiesis by TGF‐β Superfamily Signaling

“…Endoglin is differentially expressed on hematopoietic cells and was recently recognized as a marker identifying functional long-term repopulating stem cells. 60,61 The potential relevance of endoglin in hematopoiesis can be insinuated from its expression on various human hematopoietic populations, including early Bcell progenitors and erythroblasts in fetal BM, 62 pro-erythroblasts in adult BM, 62,63 CD34+ CB cells, 64 macrophages, 65 and CD4+ T-cells. 66 Additionally, studies assessing hematopoietic differentiation of murine embryonic stem cells (ESC) in vitro have shown that deletion of endoglin results in profound reduction in the formation of hemangioblasts (Fig.…”

Endoglin: a novel target for therapeutic intervention in acute leukemias revealed in xenograft mouse models

“…We have reported an important function for endoglin in cell fate specification and early hematopoiesis, [11][12][13][14][15] and a potential role beyond the embryonic stage is suggested by the expression of this receptor on the hematopoietic stem cell (HSC) isolated from every hematopoietic site, including the aorta-gonad-mesonephros, 16,17 the fetal liver, 18 and the bone marrow (BM), 19,20 in which endoglin has been reported to identify the long-term repopulating HSC. 18,19,21,22 Transcriptional profiling data of proliferating and quiescent HSCs has demonstrated endoglin to be one of the genes selectively expressed in the quiescent HSC subset. 23 Based on this evidence pointing to endoglin as a potential regulator of HSC self-renewal, we hypothesized that deregulated expression of this receptor could be associated with hematopoietic malignancies, in particular acute leukemias.…”