Biology of umbilical cord blood progenitors in bone marrow niches

Abstract

Within the bone marrow (BM), hematopoietic progenitor cells (HPCs) are localized in poorly oxygenated niches where they interact with the surrounding osteoblasts (OBs) through VLA4/VCAM-1 engagement, and are exposed to interleukin-6 (IL-6), stem cell factor (SCF), and chemokines such as CXCL12 (OB factors). Umbilical cord (UC) is more highly oxygenated that the BM microenvironment. When UC-HPCs are exposed to the 2% to 3% O 2 concentration found in the bone endosteum, their survival is significantly decreased. However, engagement of VLA-4 integrins on UCB-derived CD34 ؉ cells reduced cell death in 2% to 3% O 2 conditions, which was associated with an increase in phospho-Ser473 AKT and an increase in phospho-Ser9 GSK3b. Consistent with the role of GSK3b in destabilizing beta-catenin, there was more cytoplasmic beta-catenin in UC-HPCs exposed to 2% to 3% O 2 on fibronectin, compared with suspension culture. UC-HPCs cultured at 2% to 3% O 2 with OB factors showed an increase in nuclear betacatenin and persistence of a small pool of CD34 ؉ 38 ؊ HPCs. CFU assays followed by surface phenotyping of the plated colonies showed improved maintenance of mixed lineage colonies with both erythroid and megakaryocytic precursors. These studies provide a biologic perspective for how UC-derived HPCs adapt to the bone endosteum, which is low in oxygen and densely populated by osteoblasts. IntroductionThe bone marrow (BM) endosteum has been identified as the primary niche for primitive hematopoietic progenitor cells (p-HPCs), while the BM microvascular region serves as the site for committed HPCs (c-HPCs). [1][2][3][4][5] A longitudinal cross section of the bone shows that the endosteum is the farthest site from the bone vasculature. Consistent with this observation, the endosteum has the lowest oxygen pressure, compared with other regions within the bone. 6 It was therefore concluded that low oxygen plays a role in the maintenance of p-HPCs. Consistent with this notion, when p-HPCs are cultured under low oxygen conditions, they retain their full multilineage engraftment potential when transplanted into an irradiated recipient. 7 At the molecular level, the mechanisms by which low oxygen mitigates this effect are not fully understood, and to further delineate it was a major aim of the current study.Another important feature of the endosteum is its mesenchymal composition. 8 Compared with other regions of the bone, the endosteum has the highest number of osteoblasts, which play a role in the maintenance of p-HPCs. 9,10 Manipulation of osteoblast development in vivo directly affects the size of the p-HPC population. 11,12 Both adhesion molecules 13 and soluble factors 14,15 expressed by osteoblasts are important regulators of p-HPCs. These studies collectively suggest that 2% to 3% oxygen and osteoblast-derived factors play critical roles in p-HPC maintenance.Although it is not surprising that BM-derived p-HPCs are better maintained under low oxygen, which is a natural feature within the endosteum, it is somewhat surprising that sim...

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Xeno-free culture of human spermatogonial stem cells supported by human embryonic stem cell-derived fibroblast-like cells

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Investigating Cell Surface Markers on Normal Hematopoietic Stem Cells in Three Different Niche Conditions

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