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Cell-specific ablation of Hsp47 defines the collagen-producing cells in the injured heart
Hadi Khalil, … , Kazuhiro Nagata, Jeffery D. Molkentin
Hadi Khalil, … , Kazuhiro Nagata, Jeffery D. Molkentin
Published July 2, 2019
Citation Information: JCI Insight. 2019;4(15):e128722. https://doi.org/10.1172/jci.insight.128722.
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Research Article Cardiology

Cell-specific ablation of Hsp47 defines the collagen-producing cells in the injured heart

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Abstract

Collagen production in the adult heart is thought to be regulated by the fibroblast, although cardiomyocytes and endothelial cells also express multiple collagen mRNAs. Molecular chaperones are required for procollagen biosynthesis, including heat shock protein 47 (Hsp47). To determine the cell types critically involved in cardiac injury–induced fibrosis the Hsp47 gene was deleted in cardiomyocytes, endothelial cells, or myofibroblasts. Deletion of Hsp47 from cardiomyocytes during embryonic development or adult stages, or deletion from adult endothelial cells, did not affect cardiac fibrosis after pressure overload injury. However, myofibroblast-specific ablation of Hsp47 blocked fibrosis and deposition of collagens type I, III, and V following pressure overload as well as significantly reduced cardiac hypertrophy. Fibroblast-specific Hsp47-deleted mice showed lethality after myocardial infarction injury, with ineffective scar formation and ventricular wall rupture. Similarly, only myofibroblast-specific deletion of Hsp47 reduced fibrosis and disease in skeletal muscle in a mouse model of muscular dystrophy. Mechanistically, deletion of Hsp47 from myofibroblasts reduced mRNA expression of fibrillar collagens and attenuated their proliferation in the heart without affecting paracrine secretory activity of these cells. The results show that myofibroblasts are the primary mediators of tissue fibrosis and scar formation in the injured adult heart, which unexpectedly affects cardiomyocyte hypertrophy.

Authors

Hadi Khalil, Onur Kanisicak, Ronald J. Vagnozzi, Anne Katrine Johansen, Bryan D. Maliken, Vikram Prasad, Justin G. Boyer, Matthew J. Brody, Tobias Schips, Katja K. Kilian, Robert N. Correll, Kunito Kawasaki, Kazuhiro Nagata, Jeffery D. Molkentin

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Figure 6

Myofibroblast-specific Hsp47 deletion reduces myofibroblasts in vivo and their proliferation.

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Myofibroblast-specific Hsp47 deletion reduces myofibroblasts in vivo and...
(A) Experimental scheme whereby mice were subjected to TAC injury for 7 days. Mice received 2 i.p injections of tamoxifen and were fed tamoxifen-laden chow 48 hours before surgery and were then maintained on this chow until harvesting. Mice also received a single i.p EdU injection 4 hours before sacrifice at day 7 after TAC. (B) Representative flow cytometry plots of isolated EGFP+ interstitial cells (plotted as EGFP fluorescence signal on the x axis versus side scatter on the y axis) from hearts of the indicated genotypes of mice; 100,000 cells are displayed in the blots. (C) The ratio of total EGFP+ myofibroblasts normalized to CD31+ cells from the hearts of the indicated genotypes of mice after 1 week of TAC. Error bars represent SEM; n = 4 mice in each group. *P < 0.05 versus Postn-MCM; R26eGFP. P values were calculated with a Student’s t test. (D) Relative number of CD31+ cells in the interstitial fractions in hearts of the indicated genotypes of mice after 1 week of TAC. (E) Representative immunohistological images (scale bar: 100 μm) of EdU+ and EGFP+ interstitial cells at the time of harvest for mice treated, as shown in A. DAPI was used to show nuclei (blue). n = 5 mice in each group. (F) Quantitation of GFP+ cells that were also EdU+ in heart histological sections from mice subjected to TAC of the indicated genotype. P values were calculated with Student’s t test. #P < 0.05 versus R26eGFP Postn-MCM controls. (G) Quantitation of EdU+ Hsp47fl/fl cardiac fibroblasts over 24 hours in culture previously treated with AdCre or Adβgal infection. A total of 6 images were analyzed per group. P values were calculated with Student’s t test. #P < 0.05 versus Adβgal infection. Data shown are the mean ± SEM.

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