Exploring the State of the Science in the Field of Regenerative Medicine Challenges of and Opportunities for Cellular Therapies: Proceedings of a Workshop (2017) / Chapter Skim
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5 Cardiovascular and Lung Tissues
5 Cardiovascular and Lung Tissues
Pages 43-54
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From page 43... ...
(Gomperts) • Recently developed cells and organoids that mimic the three dimensional architecture of lung tissue may be very useful for com plex lung disease modeling and drug screening.
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From page 44... ...
This chapter explores new advances in cell and exosome-based approaches to treating heart and lung disease and includes a discussion of remaining questions and challenges that need to be addressed in order for clinical translation to take place. REPROGRAMMING APPROACHES TO CARDIOVASCULAR DISEASE In the United States, heart disease is the number one cause of death in men and women and is the leading noninfectious cause of death in children, according to Deepak Srivastava, the Younger Family Director of the Gladstone Institute of Cardiovascular Disease, the director of the Rodenberry Center for Stem Cell Biology and Medicine, and a professor at the University of California, San Francisco.
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From page 45... ...
Even in vivo the cell reprogramming process was somewhat inefficient, Srivastava said, so his team used a high-throughput screening process to identify chemical modulators that could improve the process. It was discovered that Wnt signaling and TGF-β signaling inhibitors could independently improve the efficiency, quality, and speed of direct cardiac reprogramming in vitro, and when used together they had the remarkable effect of producing beating cardiomyocytes in a cell culture dish within 1 week.
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From page 46... ...
The experimental protocol in porcine models involved inducing myocardial infarction at day 0, performing magnetic resonance imaging (MRI) to measure baseline damage at 3 days post infarction, delivering reprogramming factors via retrovirus at 5 days post infarction, and measuring cardiac function at 56 days post damage.
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From page 47... ...
Enrollment was just completed for a Phase II multi-center, randomized, placebocontrolled, double-blinded study of allogeneic CDCs in patients with mild heart failure after myocardial infarction. Other trials are under way to study allogeneic CDCs for advanced heart failure and for Duchenne muscular dystrophy–related cardiomyopathy.
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From page 48... ...
Their results have been verified in a few other models, he said, noting that CDCderived exosomes inhibited human T cell degranulation in antibodydependent cell-mediated cytotoxicity, and induced regenerative effects on skeletal muscle in the mdx mouse model of Duchenne muscular dystrophy. Although CDCs are initially derived from heart tissue, their bioactivity may be applied elsewhere in the body, Marban said.
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From page 49... ...
Capricor's business model includes a wide range of activities including discovery through development, manufacturing, regulation, and clinical trials design and management, he said. REGENERATIVE THERAPIES FOR LUNG DISEASE There is a great unmet clinical need for lung regenerative therapies, but unfortunately the field lags behind many other tissues and organ systems, said Brigitte Gomperts, an associate professor of pulmonary and pediatric medicine at the University of California, Los Angeles.
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Currently there are two Food and Drug Administration–approved drugs available for CF; however, there are subsets of patients with specific mutations who will not respond to these drugs, Gomperts said, and stem cell therapies may hold a great deal of therapeutic potential for those individuals. The strategy underlying potential cell-based therapies for CF involves generating iPS cells from patients, correcting the genetic defect in the stem cells, differentiating them into lung stem or progenitor cells, and transplanting them back into patients.
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Further examination revealed that the patient-derived iPS cells had elevated levels of cytokines and chemokines, increased levels of TGF-β activity, damage associated molecular patterns, and increased cellular stiffness -- all of which are similar to features of the lung tissue of IPF patients. These cells may be a very useful model of IPF in vitro and could be used for disease modeling as well as drug screening, Gomperts said.
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Ideally, regenerative approaches for lung diseases in the future would involve introducing a scaffold or a large amount of functional tissue back into patients, she said. PANEL DISCUSSION Partial Reprogramming A workshop participant queried the panelists about the issue of cells that only get partially reprogrammed during in vivo reprogramming.
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From page 53... ...
Cell-based therapies for lung diseases are likely not going to be solutions that use just one type of cell, Gomperts said, but instead they may be organoids or scaffolds. She said that these types of therapies are likely still very far away, but that cell-based disease modeling and drug screening are "low hanging fruit" that may be achievable in the near future.
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54 EXPLORING THE STATE OF THE SCIENCE pluripotent stem cell–derived cardiomyocytes is less of a problem today, Srivastava said. The major challenge is getting those cells to engraft and survive upon transplantation, he said.
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