Abstract
BackgroundPulmonary hypertension (PH) is a disease of multiple etiologies with several common pathological features, including inflammation and pulmonary vascular remodeling. Recent evidence has suggested a potential role for the recruitment of bone marrow-derived (BMD) progenitor cells to this remodeling process. We recently demonstrated that hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELMα) is chemotactic to murine bone marrow cells in vitro and involved in pulmonary vascular remodeling in vivo.Methodology/Principal FindingsWe used a mouse bone marrow transplant model in which lethally irradiated mice were rescued with bone marrow transplanted from green fluorescent protein (GFP)+ transgenic mice to determine the role of HIMF in recruiting BMD cells to the lung vasculature during PH development. Exposure to chronic hypoxia and pulmonary gene transfer of HIMF were used to induce PH. Both models resulted in markedly increased numbers of BMD cells in and around the pulmonary vasculature; in several neomuscularized small (∼20 µm) capillary-like vessels, an entirely new medial wall was made up of these cells. We found these GFP+ BMD cells to be positive for stem cell antigen-1 and c-kit, but negative for CD31 and CD34. Several of the GFP+ cells that localized to the pulmonary vasculature were α-smooth muscle actin+ and localized to the media layer of the vessels. This finding suggests that these cells are of mesenchymal origin and differentiate toward myofibroblast and vascular smooth muscle. Structural location in the media of small vessels suggests a functional role in the lung vasculature. To examine a potential mechanism for HIMF-dependent recruitment of mesenchymal stem cells to the pulmonary vasculature, we performed a cell migration assay using cultured human mesenchymal stem cells (HMSCs). The addition of recombinant HIMF induced migration of HMSCs in a phosphoinosotide-3-kinase-dependent manner.Conclusions/SignificanceThese results demonstrate HIMF-dependent recruitment of BMD mesenchymal-like cells to the remodeling pulmonary vasculature.
Highlights
Hypoxia-induced mitogenic factor (HIMF), known as ‘‘found in inflammatory zone 1’’ (FIZZ1) and resistin-like molecule alpha (RELMa), is a pleiotropic cytokine that is highly inducible in lung [1,2,3]
bone marrow-derived (BMD) cells are localized to the pulmonary vasculature Immunostaining for green fluorescent protein (GFP) with subsequent quantitative analysis showed that in both hypoxic and associated virus (AAV)-HIMF-treated bone marrow transplant recipients, increased numbers of GFP+ cells became associated with the vasculature (Figure 2) compared to appropriate simultaneous controls
We examined the possibility that HIMF/ FIZZ1/RELMa acts as a chemokine to induce BMD cell recruitment to the remodeling pulmonary vasculature
Summary
Hypoxia-induced mitogenic factor (HIMF), known as ‘‘found in inflammatory zone 1’’ (FIZZ1) and resistin-like molecule alpha (RELMa), is a pleiotropic cytokine that is highly inducible in lung [1,2,3]. We have shown it to have mitogenic, angiogenic, vasoconstrictive, and chemokine-like properties [3,4,5,6]. We recently demonstrated that hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELMa) is chemotactic to murine bone marrow cells in vitro and involved in pulmonary vascular remodeling in vivo
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