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Construction of Defined Human Engineered Cardiac Tissues to Study Mechanisms of Cardiac Cell Therapy
Published on: March 1, 2016
Investigating PKD2 deficiency-associated cardiomyopathies using hESC-cardiomyocytes and bioengineered 3D ventricular
Jingxuan Li1,2,3, Wentao Peng1,3, Maxwell Kwok1
1School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Hong Kong, China.
Abstract:
Autosomal dominant polycystic kidney disease is a highly prevalent hereditary renal disorder caused by mutations in either polycystin-1 or polycystin-2. These patients also develop cardiomyopathies. However, the mechanism of how polycystin-2 defects could lead to cardiomyopathies is poorly understood. Moreover, previous studies using animal models cannot fully represent human cardiomyocyte pathophysiology. Human embryonic stem cells were differentiated into cardiomyocytes. These cardiomyocytes were transduced with viral-based polycystin-2-shRNAs, then mixed with an appropriate amount of human fetal fibroblasts, collagen, and Matrigel, and biofabricated into 3D bioengineered ventricular cardiac tissue strips (hvCTS). We used these 3D hvCTS and 2D human embryonic stem cells-derived cardiomyocytes to recapitulate polycystin-2 deficiency-associated cardiac contractile defects and to explore underlying mechanisms. Knockdown of polycystin-2 decreased the contractile force and slowed down the contraction and relaxation velocities in hvCTS, indicative of contractile malfunction. The underlying mechanisms involved an elevated endoplasmic reticulum stress and a decreased activity of sarcoplasmic reticulum Ca2+-ATPases. Alleviation of endoplasmic reticulum stress by small molecular chaperones 4-phenylbutyrate/tauroursodeoxycholic acid or stimulation of sarcoplasmic reticulum Ca2+-ATPase activity by CDN1163 partially rescued the polycystin-2 deficiency-associated contractile dysfunction in hvCTS. This study used 3D hvCTS and 2D human embryonic stem cells-derived cardiomyocytes as novel disease models to recapitulate PKD2 deficiency-associated contractile defects. We found that knockdown of polycystin-2 induces cardiomyopathies via elevating endoplasmic reticulum stress and decreasing sarcoplasmic reticulum Ca2+-ATPase activity. The results provide novel insights about polycystin-2 deficiency-associated cardiomyopathies in polycystic kidney disease patients.
Insights
Polycystin-2 defects in autosomal dominant polycystic kidney disease cause heart dysfunction by increasing endoplasmic reticulum stress and reducing Ca2+-ATPase activity. Novel 3D cardiac models reveal therapeutic targets for polycystic kidney disease-associated cardiomyopathies.
Area of Science:
- Cardiovascular Biology
- Renal Pathophysiology
- Stem Cell Biology
Background:
- Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder caused by mutations in polycystin genes.
- ADPKD patients frequently develop cardiomyopathies, but the underlying mechanisms involving polycystin-2 are not well understood.
- Existing animal models do not fully replicate human cardiomyocyte dysfunction in ADPKD.
Purpose of the Study:
- To investigate the mechanisms by which polycystin-2 deficiency leads to cardiac contractile defects.
- To develop and utilize novel 3D human cardiac tissue models for studying ADPKD-associated cardiomyopathies.
- To explore potential therapeutic interventions for polycystin-2 deficiency-related heart conditions.
Main Methods:
- Human embryonic stem cells were differentiated into cardiomyocytes.
- Polycystin-2 was knocked down using shRNAs in cardiomyocytes, which were then biofabricated into 3D engineered ventricular cardiac tissue strips (hvCTS).
- Cardiac function, endoplasmic reticulum stress markers, and sarcoplasmic reticulum Ca2+-ATPase activity were assessed in 2D and 3D models.
Main Results:
- Knockdown of polycystin-2 in hvCTS significantly reduced cardiac contractility and slowed contraction/relaxation velocities.
- Polycystin-2 deficiency led to increased endoplasmic reticulum stress and decreased sarcoplasmic reticulum Ca2+-ATPase activity.
- Treatment with molecular chaperones or a Ca2+-ATPase activator partially restored cardiac function in the polycystin-2 deficient models.
Conclusions:
- Polycystin-2 deficiency in ADPKD causes cardiomyopathy through elevated endoplasmic reticulum stress and impaired sarcoplasmic reticulum Ca2+-ATPase function.
- Novel 3D cardiac tissue models effectively recapitulate ADPKD-associated cardiac defects.
- Targeting endoplasmic reticulum stress and Ca2+-ATPase activity may offer therapeutic strategies for ADPKD-related cardiomyopathies.
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