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Heart repair by reprogramming non-myocytes with cardiac transcription factors.

Song K, Nam YJ, Luo X, Qi X, Tan W, Huang GN, Acharya A, Smith CL, Tallquist MD, Neilson EG, Hill JA, Bassel-Duby R, Olson EN - Nature (2012)

Bottom Line: Fibrosis due to activation of cardiac fibroblasts impedes cardiac regeneration and contributes to loss of contractile function, pathological remodelling and susceptibility to arrhythmias.Forced expression of these factors in dividing non-cardiomyocytes in mice reprograms these cells into functional cardiac-like myocytes, improves cardiac function and reduces adverse ventricular remodelling following myocardial infarction.Our results suggest a strategy for cardiac repair through reprogramming fibroblasts resident in the heart with cardiogenic transcription factors or other molecules.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas 75390-9148, USA.

ABSTRACT
The adult mammalian heart possesses little regenerative potential following injury. Fibrosis due to activation of cardiac fibroblasts impedes cardiac regeneration and contributes to loss of contractile function, pathological remodelling and susceptibility to arrhythmias. Cardiac fibroblasts account for a majority of cells in the heart and represent a potential cellular source for restoration of cardiac function following injury through phenotypic reprogramming to a myocardial cell fate. Here we show that four transcription factors, GATA4, HAND2, MEF2C and TBX5, can cooperatively reprogram adult mouse tail-tip and cardiac fibroblasts into beating cardiac-like myocytes in vitro. Forced expression of these factors in dividing non-cardiomyocytes in mice reprograms these cells into functional cardiac-like myocytes, improves cardiac function and reduces adverse ventricular remodelling following myocardial infarction. Our results suggest a strategy for cardiac repair through reprogramming fibroblasts resident in the heart with cardiogenic transcription factors or other molecules.

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Attenuation of fibrosis in response to MI by GHMTa. Comparison of cardiac fibrosis and scar formation between GFP and GHMT infected myocardium 4 weeks after LAD ligation. Cardiac fibrosis was evaluated at 5 levels (L1–L5) by trichrome staining 4 weeks post-MI. The ligation site is marked as X. Severity of cardiac fibrosis was classified as mild, moderate or severe (fibrotic area <20%, 20–40% or >40%, respectively). Numbers indicate the various type of severity/total number of hearts examined in each group. A graph shows animal distribution in each category. Scale bar, 1mm. b. Quantification of fibrotic area in heart sections displayed in (a). Fibrotic area (%) = (the sum of fibrotic area at levels 3 and 4/the sum of myocardial area in the LV at levels 3 and 4) × 100. Data are presented as mean ± std. *: p<0.05, **: p<0.005.
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Figure 5: Attenuation of fibrosis in response to MI by GHMTa. Comparison of cardiac fibrosis and scar formation between GFP and GHMT infected myocardium 4 weeks after LAD ligation. Cardiac fibrosis was evaluated at 5 levels (L1–L5) by trichrome staining 4 weeks post-MI. The ligation site is marked as X. Severity of cardiac fibrosis was classified as mild, moderate or severe (fibrotic area <20%, 20–40% or >40%, respectively). Numbers indicate the various type of severity/total number of hearts examined in each group. A graph shows animal distribution in each category. Scale bar, 1mm. b. Quantification of fibrotic area in heart sections displayed in (a). Fibrotic area (%) = (the sum of fibrotic area at levels 3 and 4/the sum of myocardial area in the LV at levels 3 and 4) × 100. Data are presented as mean ± std. *: p<0.05, **: p<0.005.

Mentions: To determine whether functional improvement was sustained, we assessed cardiac function at 6 weeks and 12 weeks by EF and stroke volume using cardiac MRI. EF of GFP-injected mice decreased to reach a stable value of ~28% 6 weeks post-MI (Fig. 4b). In contrast, infection of injured myocardium with GHMT blunted worsening of EF 6 weeks post-MI (~49%) with further significant improvement at 12 weeks post-MI (~57%) (Fig. 4b). This long-term effect on EF by GHMT was accompanied by significant increases in stroke volume at 12 weeks compared to 6 weeks (Fig. 4b). Individual mice in each group demonstrated similar functional changes in both cardiac parameters, indicating the reliability of cardiac MRI to assess cardiac function (Supplementary Fig. 19). These data suggest that expression of GHMT in non-cardiomyocytes in injured hearts can sustain cardiac function. Moreover, GHMT- and GHMMsT-infected hearts showed a pronounced reduction in fibrosis and increased muscle tissue, compared with GFP-infected hearts after MI (Fig. 5a, b and Supplementary Fig. 20).


Heart repair by reprogramming non-myocytes with cardiac transcription factors.

Song K, Nam YJ, Luo X, Qi X, Tan W, Huang GN, Acharya A, Smith CL, Tallquist MD, Neilson EG, Hill JA, Bassel-Duby R, Olson EN - Nature (2012)

Attenuation of fibrosis in response to MI by GHMTa. Comparison of cardiac fibrosis and scar formation between GFP and GHMT infected myocardium 4 weeks after LAD ligation. Cardiac fibrosis was evaluated at 5 levels (L1–L5) by trichrome staining 4 weeks post-MI. The ligation site is marked as X. Severity of cardiac fibrosis was classified as mild, moderate or severe (fibrotic area <20%, 20–40% or >40%, respectively). Numbers indicate the various type of severity/total number of hearts examined in each group. A graph shows animal distribution in each category. Scale bar, 1mm. b. Quantification of fibrotic area in heart sections displayed in (a). Fibrotic area (%) = (the sum of fibrotic area at levels 3 and 4/the sum of myocardial area in the LV at levels 3 and 4) × 100. Data are presented as mean ± std. *: p<0.05, **: p<0.005.
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Related In: Results  -  Collection

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Figure 5: Attenuation of fibrosis in response to MI by GHMTa. Comparison of cardiac fibrosis and scar formation between GFP and GHMT infected myocardium 4 weeks after LAD ligation. Cardiac fibrosis was evaluated at 5 levels (L1–L5) by trichrome staining 4 weeks post-MI. The ligation site is marked as X. Severity of cardiac fibrosis was classified as mild, moderate or severe (fibrotic area <20%, 20–40% or >40%, respectively). Numbers indicate the various type of severity/total number of hearts examined in each group. A graph shows animal distribution in each category. Scale bar, 1mm. b. Quantification of fibrotic area in heart sections displayed in (a). Fibrotic area (%) = (the sum of fibrotic area at levels 3 and 4/the sum of myocardial area in the LV at levels 3 and 4) × 100. Data are presented as mean ± std. *: p<0.05, **: p<0.005.
Mentions: To determine whether functional improvement was sustained, we assessed cardiac function at 6 weeks and 12 weeks by EF and stroke volume using cardiac MRI. EF of GFP-injected mice decreased to reach a stable value of ~28% 6 weeks post-MI (Fig. 4b). In contrast, infection of injured myocardium with GHMT blunted worsening of EF 6 weeks post-MI (~49%) with further significant improvement at 12 weeks post-MI (~57%) (Fig. 4b). This long-term effect on EF by GHMT was accompanied by significant increases in stroke volume at 12 weeks compared to 6 weeks (Fig. 4b). Individual mice in each group demonstrated similar functional changes in both cardiac parameters, indicating the reliability of cardiac MRI to assess cardiac function (Supplementary Fig. 19). These data suggest that expression of GHMT in non-cardiomyocytes in injured hearts can sustain cardiac function. Moreover, GHMT- and GHMMsT-infected hearts showed a pronounced reduction in fibrosis and increased muscle tissue, compared with GFP-infected hearts after MI (Fig. 5a, b and Supplementary Fig. 20).

Bottom Line: Fibrosis due to activation of cardiac fibroblasts impedes cardiac regeneration and contributes to loss of contractile function, pathological remodelling and susceptibility to arrhythmias.Forced expression of these factors in dividing non-cardiomyocytes in mice reprograms these cells into functional cardiac-like myocytes, improves cardiac function and reduces adverse ventricular remodelling following myocardial infarction.Our results suggest a strategy for cardiac repair through reprogramming fibroblasts resident in the heart with cardiogenic transcription factors or other molecules.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas 75390-9148, USA.

ABSTRACT
The adult mammalian heart possesses little regenerative potential following injury. Fibrosis due to activation of cardiac fibroblasts impedes cardiac regeneration and contributes to loss of contractile function, pathological remodelling and susceptibility to arrhythmias. Cardiac fibroblasts account for a majority of cells in the heart and represent a potential cellular source for restoration of cardiac function following injury through phenotypic reprogramming to a myocardial cell fate. Here we show that four transcription factors, GATA4, HAND2, MEF2C and TBX5, can cooperatively reprogram adult mouse tail-tip and cardiac fibroblasts into beating cardiac-like myocytes in vitro. Forced expression of these factors in dividing non-cardiomyocytes in mice reprograms these cells into functional cardiac-like myocytes, improves cardiac function and reduces adverse ventricular remodelling following myocardial infarction. Our results suggest a strategy for cardiac repair through reprogramming fibroblasts resident in the heart with cardiogenic transcription factors or other molecules.

Show MeSH
Related in: MedlinePlus