Trafficking of Murine Hematopoietic Stem and Progenitor Cells in Health and Vascular Disease

Hematopoietic stem cells (HSCs) possess the unique capacity for self‐renewal and differentiation into various hematopoietic cell lineages. Here we summarize the processes that underlie their mobilization and directed migration from bone marrow into peripheral tissues and back to the bone marrow compartment. We specifically focus on the potential role of hematopoietic stem and progenitor cell (HSPC) migration in vascular diseases and review data from recent studies on mice. A better understanding of the mechanisms that guide HSPCs to vascular tissues will be critical for the development of novel therapeutic strategies to prevent or reverse cardiovascular diseases.     

Circulating Hematopoietic Progenitor Cells are Decreased in COPD

Rationale: Bone marrow derived progenitor cells participate in the repair of injured vessels. The lungs of individuals with emphysema have reduced alveolar capillary density and increased endothelial apoptosis. We hypothesized that circulating levels of endothelial and hematopoietic progenitor cells would be reduced in this group of patients. Objectives: The goal of this study was to measure circulating levels of endothelial progenitor cells (EPCs) and hematopoietic progenitor cells (HPCs) in subjects with COPD and to determine if progenitor levels correlated with disease severity and the presence of emphysema. Methods: Peripheral blood mononuclear cells were isolated from 61 patients with COPD and 32 control subjects. Levels of EPCs (CD45^dim CD34₊) and HPCs (CD45⁺ CD34⁺ VEGF-R2⁺) were quantified using multi-parameter flow cytometry. Progenitor cell function was assessed using cell culture assays. All subjects were evaluated with spirometry and CT scanning. Measurements and Main Results: HPC levels were reduced in subjects with COPD compared to controls, whereas circulating EPC levels were similar between the two groups. HPC levels correlated with severity of obstruction and were lowest in subjects with severe emphysema. These associations remained after correction for factors known to affect progenitor cell levels including age, smoking status, the use of statin medications and the presence of coronary artery disease. The ability of mononuclear cells to form endothelial cell colony forming units (EC-CFU) was also reduced in subjects with COPD. Conclusions: HPC levels are reduced in subjects with COPD and correlate with emphysema phenotype and severity of obstruction. Reduction of HPCs may disrupt maintenance of the capillary endothelium, thereby contributing to the pathogenesis of COPD.     

Overexpression of Interleukin 21 Induces Expansion of Hematopoietic Progenitor Cells

The interleukin 21 (IL-21) receptor is expressed on T-cells, B-cells, and natural killer cells, and IL-21 is critical for regulating immunoglobulin production in vivo in cooperation with IL-4. So far, however, little is known about a role for IL-21 outside the immune system. We investigated the effect of IL-21 on hematopoiesis in vivo by using the hydrodynamics gene-delivery method. Overexpression of IL-21 increases Sca-1+ cells in the periphery and spleen. It also increases the numbers of c-Kit+, Sca-1+, and lineage-/low (KSL) cells and colony-forming units-granulocyte-macrophage (CFU-GM) in the spleen, indicating the expansion of hematopoietic progenitor cells. We found that even in RAG2-/- mice, which lack mature T-cells and B-cells, IL-21 induced an increase in KSL cells and CFU-GM in the spleen. These results demonstrate that IL-21 can induce the expansion of hematopoietic progenitor cells in vivo, even in the absence of mature T-cells and B-cells.     

内皮素促进细胞增殖相关基因的表达和血管平滑肌细胞增殖

通过３Ｈ－ＴｄＲ掺入实验和ＲＮＡ印迹分析，观察了内皮素－１对大鼠血管平滑肌细胞ＤＮＡ合成及细胞增殖相关基因表达的影响。结果表明，内皮素－１作用于血管平滑肌细胞１２ｈ，３Ｈ－ＴｄＲ掺入开始增加，２４ｈ达到峰值。在内皮素－１作用下，原癌基因ｃ－ｆｏｓ和ｃ－ｊｕｎ进行快速瞬间表达，其表达活性在３０ｍｉｎ达到峰值，３ｈ后恢复到原来水平；Ｐ３４＾激酶基因在内皮素－１刺激１２ｈ后表达活性开始增加，至２４ｈ仍维     

Production of Monocyte Chemotactic Protein-1 (MCP-1/JE) by Bone Marrow Stromal Cells: Effect on the Migration and Proliferation of Hematopoietic Progenitor Cells

Recombinant chemotactic cytokines (chemokines) have been shown to modulate in vitro proliferation of hematopoietic progenitor cells. Whether bone marrow stromal cells produce chemokines and the physiological role they may have in the regulation of hematopoiesis has largely remained unexamined. We have examined the expression of monocyte chemoattractant protein-1 (MCP-1/JE) in bone marrow stromal cells and its effect on the migration and proliferation of murine hematopoietic progenitor cells. Freshly derived murine bone marrow stromal cells were found to secrete abundant amounts of MCP-1/JE, which was further increased upon stimulation of stromal cells with pro-inflammatory agents LPS, IL1-α, IFN-γ, or TNF-α. Although culture supernatant conditioned by stromal cells exhibited chemotactic activity toward hematopoietic progenitor cells, the chemotactic activity was not due to MCP-1/JE. Furthermore, rMCP-1/JE also failed to induce migration of progenitor cells. MCP-1/JE, however, caused 20 to 30% increase in the clonal expansion of progenitor cells. Thus, although MCP-1/JE does not chemoattract hematopoietic progenitor cells it may have a role in their proliferation and clonal expansion.     

Lack of Recovery of Murine Hematopoietic Stromal Cells After Irradiation-induced Damage

The rates of recovery of colony-formingunits (CFU) and of hematopoietic stromafollowing x-irradiation were compared.Hematopoietic stromal function of femursand spleens was assessed by assaying thenumber of CFU in those sites 6 wk afterimplanting them subcutaneously into isogeneic hosts. Whereas the number of CFUreturned to preirradiation levels in 6 wk,the hematopoietic stroma did not recoversignificantly in 9 wk. The reasons forregeneration of CFU in a defective stromawere next investigated. Two contributingfactors were identified: (1) Stromal damage following 950 rads is such as to retard the rate of regeneration of CFU without significantly limiting the eventualnumber of CFU in the site, and (2) Radiated mice contain factor(s), possiblyhumoral, which accelerate the rate ofregeneration of CFU.

Submitted on January 8, 1974 Accepted on March 29, 1974