Bone Marrow–Derived Cells Are Involved in the Pathogenesis of Cardiac Hypertrophy in Response to Pressure Overload

Abstract

Background-Bone marrow (BM) cells possess broad differentiation potential and can form various cell lineages in response to pathophysiological cues. The present study investigated whether BM-derived cells contribute to the pathogenesis of cardiac hypertrophy, as well as the possible cellular mechanisms involved in such a role. Methods and Results-Lethally irradiated wild-type mice were transplanted with BM cells from enhanced green fluorescent protein-transgenic mice. The chimeric mice were subjected to either prolonged hypoxia or transverse aortic constriction. BM-derived enhanced green fluorescent protein-expressing cardiomyocytes increased in number over time, emerging predominantly in the pressure-overloaded ventricular myocardium, although they constituted Ͻ0.01% of recipient cardiomyocytes. To determine whether BM-derived cardiomyocytes were derived from cell fusion or transdifferentiation at the single-cell level, lethally irradiated Cre mice were transplanted with BM cells from the double-conditional Cre reporter mouse line Z/EG. BM-derived cardiomyocytes were shown to arise from both cell fusion and transdifferentiation. Interestingly, BM-derived myofibroblasts expressing both vimentin and ␣-smooth muscle actin were concentrated in the perivascular fibrotic area. These cells initially expressed MAC-1/CD14 but lost expression of these markers during the chronic phase, which suggests that they were derived from monocytes. A similar phenomenon occurred in cultured human monocytes, most of which ultimately expressed vimentin and ␣-smooth muscle actin. Conclusions-We found that BM-derived cells were involved in the pathogenesis of cardiac hypertrophy via the dual mechanisms of cell fusion and transdifferentiation. Moreover, the present results suggest that BM-derived monocytes accumulating in the perivascular space might play an important role in the formation of perivascular fibrosis via direct differentiation into myofibroblasts.

Cardiac fibrosis in mice with hypertrophic cardiomyopathy is mediated by non-myocyte proliferation and requires Tgf-β

“…Fsp1 but not α-smooth muscle actin was found in non-myocyte cells from hypertrophic hearts ( Figure 1C). Activated non-myocyte cells may also be derived from circulating cells (14,(46)(47)(48). Alternatively, the enhanced biomechanical forces resulting from sarcomere protein mutations (7,8) could also provide a local mechanism for activating resident non-myocyte cells.…”

Prorenin Receptor Is Essential for Normal Podocyte Structure and Function

“…Sections (4 m) were mounted on gelatin-coated slides and were stained immunochemically as described previously. 34 The immunofluorescence of cultured cells was determined as described previously. 35 Podocytes were observed 8 days after the transfection of ATP6AP2 siRNA and 12 hours after treatment with chloroquine and Carl Zeiss, Oberkochen, Germany).…”

Myocardial fibrosis in response to Angiotensin II is preceded by the recruitment of mesenchymal progenitor cells

“…22 Briefly, BM cells were harvested from 8-week-old eGFP-transgenic mice with a C57Bl/6 background. 22 After irradiation with a two doses of 5.5 Gy, 4 h apart, the unfractionated GFP þ BM cells (5 Â 10 6 cells in 150 ml of sterile phosphate-buffered saline) were injected via the tail vein into irradiated C57/Bl6 mice. Engraftment was evaluated 8 weeks later by collecting peripheral blood cells and looking at the frequency of GFP þ cells among peripheral nucleated cells (data not shown).…”

“…Engraftment was evaluated 8 weeks later by collecting peripheral blood cells and looking at the frequency of GFP þ cells among peripheral nucleated cells (data not shown). 22,23 Only animals with demonstrated engraftment (460% of white blood cells were GFP þ ) were used for the two treatment groups (saline control or AngII infusion as per protocol). Immunofluorescence was used to enhance localize GFP þ cells within the myocardium.…”