The need for developing effective treatment modalities for the injured and failing heart is expanding, as cardiac disease continues to take more human lives than all cancer combined. Cardiac muscle generated from human induced pluripotent stem cells (iPSCs) could serve as a model for studies of heart injury and regeneration, if the tissue would be mature enough to acquire adult-like phenotype. The lack of maturity and patient specificity are limiting the utility of currently available models. Three advances, achieved in our labs during our previous grant cycle and recent preliminary studies, form basis for the proposed new approach to studies of cardiac injury and regeneration: (a) Adult-like human cardiac muscle grown from human iPSCs (Ronaldson-Bouchard et al, Nature); (b) Perfusable network of channels serving as a template for vascularized tissues (Zhang et al, Nature Materials 2016) and (c) Heart regeneration in an animal model using human iPS-CM derived exosomes (Liu et al, Nature Biomedical Engineering, 2018). We propose to build upon these advances and bioengineer patient-specific vascularized human heart muscle using iPSCs from diverse populations, and study the individual differences under normal conditions, following ischemic injury, and during regeneration. We will focus on the racial background and sex as major risk factors for cardiovascular disease. Another important focus of the proposed studies is on the cell-secreted vesicles (exosomes) and their mRNA cargo, both as the readouts of cell state (e.g., during injury and regeneration) and as a cell-free therapeutic modality for ischemic heart. We hypothesize that the mature vascularized cardiac muscle generated from iPS cells from diverse patient populations (female vs male; African-American vs white) will be able to capture clinically observed differences in responses to cardiac ischemia, and that we will be able to specifically address these differences by sustained delivery of patient-tailored exosomes. To test this hypothesis, we propose three specific aims that will be pursued in an integrated fashion, with the outcomes of each aim informing the other two aims.
Aim 1 is to engineer adult-like vascularized cardiac muscle from patient-specific iPSCs.
Aim 2 is to develop an in vitro model of cardiac injury-regeneration using patient-specific iPSCs.
Aim 3 is to establish mechanisms of exosome mediated signaling. We believe that this work will have impact on quantitative biological research and the development of bioengineering modalities for treating heart disease.

Public Health Relevance

Heart disease continues to take more human lives than all cancer combined, prompting the need to improve regeneration of injured heart muscle. We propose a novel tissue engineering approach to form an adult-like human heart muscle, that will be used to study heart injury and therapeutic modalities for heart regeneration. This work would advance fundamental research and lead to new modalities for treating heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL076485-12
Application #
9670592
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Lundberg, Martha
Project Start
2005-07-01
Project End
2022-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
12
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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Savoji, Houman; Mohammadi, Mohammad Hossein; Rafatian, Naimeh et al. (2018) Cardiovascular disease models: A game changing paradigm in drug discovery and screening. Biomaterials :
Chen, Timothy; Vunjak-Novakovic, Gordana (2018) In vitro Models of Ischemia-Reperfusion Injury. Regen Eng Transl Med 4:142-153
Liu, Bohao; Lee, Benjamin W; Nakanishi, Koki et al. (2018) Cardiac recovery via extended cell-free delivery of extracellular vesicles secreted by cardiomyocytes derived from induced pluripotent stem cells. Nat Biomed Eng 2:293-303
Korolj, Anastasia; Laschinger, Carol; James, Chris et al. (2018) Curvature facilitates podocyte culture in a biomimetic platform. Lab Chip 18:3112-3128
Ronaldson-Bouchard, Kacey; Vunjak-Novakovic, Gordana (2018) Organs-on-a-Chip: A Fast Track for Engineered Human Tissues in Drug Development. Cell Stem Cell 22:310-324
Jay, Steven M; Vunjak-Novakovic, Gordana (2017) * Extracellular Vesicles and Their Versatile Roles in Tissue Engineering. Tissue Eng Part A 23:1210-1211
Yuan, Xiaoning; Wei, Yiyong; Villasante, Aránzazu et al. (2017) Stem cell delivery in tissue-specific hydrogel enabled meniscal repair in an orthotopic rat model. Biomaterials 132:59-71
Conant, Genevieve; Ahadian, Samad; Zhao, Yimu et al. (2017) Kinase inhibitor screening using artificial neural networks and engineered cardiac biowires. Sci Rep 7:11807
Reis, Lewis A; Chiu, Loraine L Y; Feric, Nicole et al. (2016) Biomaterials in myocardial tissue engineering. J Tissue Eng Regen Med 10:11-28

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