Bone marrow-derived cells are involved in the pathogenesis of cardiac hypertrophy in response to pressure overload

Jin Endo, Motoaki Sano, Jun Fujita, Kentaro Hayashida, Shinsuke Yuasa, Naoki Aoyama, Yuji Takehara, Osamu Kato, Shinji Makino, Satoshi Ogawa, Keiichi Fukuda

Research output: Contribution to journalArticle

40 Citations (Scopus)

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 <0.01% 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 α-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 α-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.

Original languageEnglish
Pages (from-to)1176-1184
Number of pages9
JournalCirculation
Volume116
Issue number10
DOIs
Publication statusPublished - 2007 Sep

Fingerprint

Cardiomegaly
Bone Marrow Cells
Cell Transdifferentiation
Cardiac Myocytes
Bone Marrow
Cell Fusion
Pressure
Monocytes
Myofibroblasts
Vimentin
Smooth Muscle
Actins
Cell Lineage
Ventricular Pressure
Constriction
Transgenic Mice
Cues
Myocardium
Fibrosis
enhanced green fluorescent protein

Keywords

  • Bone marrow
  • Cell fusion
  • Fibroblasts
  • Hypertrophy

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Bone marrow-derived cells are involved in the pathogenesis of cardiac hypertrophy in response to pressure overload. / Endo, Jin; Sano, Motoaki; Fujita, Jun; Hayashida, Kentaro; Yuasa, Shinsuke; Aoyama, Naoki; Takehara, Yuji; Kato, Osamu; Makino, Shinji; Ogawa, Satoshi; Fukuda, Keiichi.

In: Circulation, Vol. 116, No. 10, 09.2007, p. 1176-1184.

Research output: Contribution to journalArticle

Endo, Jin ; Sano, Motoaki ; Fujita, Jun ; Hayashida, Kentaro ; Yuasa, Shinsuke ; Aoyama, Naoki ; Takehara, Yuji ; Kato, Osamu ; Makino, Shinji ; Ogawa, Satoshi ; Fukuda, Keiichi. / Bone marrow-derived cells are involved in the pathogenesis of cardiac hypertrophy in response to pressure overload. In: Circulation. 2007 ; Vol. 116, No. 10. pp. 1176-1184.
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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 <0.01{\%} 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 α-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 α-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.",
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T1 - Bone marrow-derived cells are involved in the pathogenesis of cardiac hypertrophy in response to pressure overload

AU - Endo, Jin

AU - Sano, Motoaki

AU - Fujita, Jun

AU - Hayashida, Kentaro

AU - Yuasa, Shinsuke

AU - Aoyama, Naoki

AU - Takehara, Yuji

AU - Kato, Osamu

AU - Makino, Shinji

AU - Ogawa, Satoshi

AU - Fukuda, Keiichi

PY - 2007/9

Y1 - 2007/9

N2 - 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 <0.01% 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 α-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 α-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.

AB - 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 <0.01% 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 α-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 α-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.

KW - Bone marrow

KW - Cell fusion

KW - Fibroblasts

KW - Hypertrophy

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U2 - 10.1161/CIRCULATIONAHA.106.650903

DO - 10.1161/CIRCULATIONAHA.106.650903

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