Heart Disease

Coding Dimension ID: 
295
Coding Dimension path name: 
Heart Disease

Center of Excellence for Stem Cell Genomics

Funding Type: 
Genomics Centers of Excellence Awards (R)
Grant Number: 
GC1R-06673-A
ICOC Funds Committed: 
$40 000 000
Disease Focus: 
Brain Cancer
Cancer
Developmental Disorders
Heart Disease
Cancer
Genetic Disorder
Stem Cell Use: 
iPS Cell
Embryonic Stem Cell
Adult Stem Cell
Cancer Stem Cell
Cell Line Generation: 
iPS Cell
Public Abstract: 
The Center of Excellence in Stem Cell Genomics will bring together investigators from seven major California research institutions to bridge two fields – genomics and pluripotent stem cell research. The projects will combine the strengths of the center team members, each of whom is a leader in one or both fields. The program directors have significant prior experience managing large-scale federally-funded genomics research programs, and have published many high impact papers on human stem cell genomics. The lead investigators for the center-initiated projects are expert in genomics, hESC and iPSC derivation and differentiation, and bioinformatics. They will be joined by leaders in stem cell biology, cancer, epigenetics and computational systems analysis. Projects 1-3 will use multi-level genomics approaches to study stem cell derivation and differentiation in heart, tumors and the nervous system, with implications for understanding disease processes in cancer, diabetes, and cardiac and mental health. Project 4 will develop novel tools for computational systems and network analysis of stem cell genome function. A state-of-the-art data management program is also proposed. This research program will lead the way toward development of the safe use of stem cells in regenerative medicine. Finally, Center resources will be made available to researchers throughout the State of California through a peer-reviewed collaborative research program.
Statement of Benefit to California: 
Our Center of Excellence for Stem Cell Genomics will help California maintain its position at the cutting edge of Stem Cell research and greatly benefit California in many ways. First, diseases such as cardiovascular disease, cancer, neurological diseases, etc., pose a great financial burden to the State. Using advanced genomic technologies we will learn how stem cells change with growth and differentiation in culture and can best be handled for their safe use for therapy in humans. Second, through the collaborative research program, the center will provide genomics services to investigators throughout the State who are studying stem cells with a goal of understanding and treating specific diseases, thereby advancing treatments. Third, it will employ a large number of “high tech” individuals, thereby bringing high quality jobs to the state. Fourth, since many investigators in this center have experience in founding successful biotech companies it is likely to “spin off” new companies in this rapidly growing high tech field. Fifth, we believe that the iPS and information resources generated by this project will have significant value to science and industry and be valuable for the development of new therapies. Overall, the center activities will create a game-changing network effect for the state, propelling technology development, biological discovery and disease treatment in the field.

Metabolic regulation of cardiac differentiation and maturation

Funding Type: 
Basic Biology V
Grant Number: 
RB5-07356
ICOC Funds Committed: 
$1 124 834
Disease Focus: 
Heart Disease
Stem Cell Use: 
Embryonic Stem Cell
iPS Cell
oldStatus: 
Closed
Public Abstract: 
Cells in the body take up nutrients from their environment and metabolize them in a complex set of biochemical reactions to generate energy and replicate. Control of these processes is particularly important for heart cells, which need large amounts of energy to drive blood flow throughout the body. Not surprisingly, the nutritional requirements of heart cells are very different than those of stem cells. This proposal will investigate the metabolism of pluripotent stem cells and how this changes during differentiation to cardiac cells. We will determine which nutrients are important to make functional heart cells and use this information to optimize growth conditions for producing heart cells for regenerative medicine and basic biology applications. We accomplish this by feeding cells nutrients (sugar, fat) labeled with isotopes. As these labeled molecules are consumed, the isotopes are incorporated into different metabolites which we track using mass spectrometry. This advanced technique will allow us to see how sugars and fat are metabolized inside stem cells and cardiac cells obtained through differentiation. We will also study the electrical activity of these heart cells to ensure that adequate nutrients are provided for the generation of cells with optimal function. Ultimately, this project will lead to new methods for producing functional heart cells for regenerative medicine and may also lead to insights into how cardiac cells malfunction in heart disease.
Statement of Benefit to California: 
Heart disease is one of the leading causes of death in California. As a result, much of the regenerative medicine community in the state and the many Californians suffering from heart failure are interested in obtaining functional heart cells from stem cells. Our work will identify the most important nutrients required to coax stem cell-derived heart cells to behave like true adult heart cells. This information will make more effective cell models for researchers and companies to study how this disease affects heart cell metabolism. Since enzymes are highly targetable with drugs, the basic scientific findings from our work will be of great interest to California biotechnology companies and can stimulate job growth in the state. Our findings will also provide insight into very specific types of genetic heart disease, and this work may lead to additional grants from federal funding sources, bringing about additional revenue and job growth in California. A better understanding of how different nutrients influence heart cell function may provide guidance into new treatment strategies for heart disease. Finally, this work will highlight the importance of diet, nutrition, and healthy heart function, providing useful information relating to public health.

Improving Existing Drugs for Long QT Syndrome type 3 (LQT3) by hiPSC Disease-in-Dish Model

Funding Type: 
Early Translational IV
Grant Number: 
TR4-06857
ICOC Funds Committed: 
$6 361 618
Disease Focus: 
Heart Disease
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
This project uses patient hiPSC-derived cardiomyocytes to develop a safe and effective drug to treat a serious heart health condition. This research and product development will provide a novel method for a human genetic heart disorder characterized by long delay (long Q-T interval) between heart beats caused by mutations in the Na+ channel α subunit. Certain patients are genetically predisposed to a potentially fatal arrhythmogenic response to existing drugs to treat LQT3 since the drugs have off-target effects on other important ion channels in cardiomyocytes. We will use patient-derived hiPSC-cardiomyocytes to develop a safer drug (development candidate, DC) that will retain efficacy against the "leaky" Na+-channel yet minimize off-target effects in particular against the K+ hERG channel that can be responsible for the existing drug’s pro-arrhythmic effect. Since this problem is thought to occur severely in patients with the common KCHN2 variant, K897T (~33% of the white population), removing the off-target liability addresses a serious unmet clinical need. Futher, since we propose to modify an existing drug (i.e., do drug rescue), the path from patient-specific hiPSCs to clinic might be easier than for a completely new chemical entity. Lastly, an appealing aspect is that the hiPSCs were derived from a child to test his therapy, & we aim to produce a better drug for his treatment. Our goal is to complete development of the DC and initiate IND-enabling in vivo studies.
Statement of Benefit to California: 
In the US, an estimated 850,000 adults are hospitalized for arrhythmias each year, making arrhythmias one of the top five causes of healthcare expenditures in the US with a direct cost of more than $40 billion annually for diagnosis, treatment & rehabilitation. The State of California has approximately 12% of the US population which translates to 102,000 individuals hospitalized every year for arrhythmias. Another 30,000 Californians die of sudden arrhythmic death syndrome every year. Arrhythmias are very common in older adults and because the population of California is aging, research to address this issue is important for human health and the State economy. Most serious arrhythmias affect people older than 60. This is because older adults are more likely to have heart disease & other health problems that can lead to arrhythmias. Older adults also tend to be more sensitive to the side effects of medicines, some of which can cause arrhythmias. Some medicines used to treat arrhythmias can even cause arrhythmias as a side effect. In the US, atrial fibrillation (a common type of arrhythmia that can cause problems) affects millions of people & the number is rising. Accordingly, the same problem is present in California. Thus, successful completion of this work will not only provide citizens of California much needed advances in cardiovascular health technology & improvement in health care but an improved heart drug. This will provide high paying jobs & significant tax revenue.

The CIRM Human Pluripotent Stem Cell Biorepository – A Resource for Safe Storage and Distribution of High Quality iPSCs

Funding Type: 
hPSC Repository
Grant Number: 
IR1-06600
ICOC Funds Committed: 
$9 999 834
Disease Focus: 
Developmental Disorders
Heart Disease
Infectious Disease
Alzheimer's Disease
Neurological Disorders
Autism
Respiratory Disorders
Vision Loss
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
Critical to the long term success of the CIRM iPSC Initiative of generating and ensuring the availability of high quality disease-specific human IPSC lines is the establishment and successful operation of a biorepository with proven methods for quality control, safe storage and capabilities for worldwide distribution of high quality, highly-characterized iPSCs. Specifically the biorepository will be responsible for receipt, expansion, quality characterization, safe storage and distribution of human pluripotent stem cells generated by the CIRM stem cell initiative. This biobanking resource will ensure the availability of the highest quality hiPSC resources for researchers to use in disease modeling, target discovery and drug discovery and development for prevalent, genetically complex diseases.
Statement of Benefit to California: 
The generation of induced pluripotent stem cells (iPSCs) from patients and subsequently, the ability to differentiate these iPSCs into disease-relevant cell types holds great promise in facilitating the “disease-in-a-dish” approach for studying our understanding of the pathological mechanisms of human disease. iPSCs have already proven to be a useful model for several monogenic diseases such as Parkinson’s, Fragile X Syndrome, Schizophrenia, Spinal Muscular Atrophy, and inherited metabolic diseases such as 1-antitrypsin deficiency, familial hypercholesterolemia, and glycogen storage disease. In addition, the differentiated cells obtained from iPSCs represent a renewable, disease-relevant cell model for high-throughput drug screening and toxicology/safety assessment which will ultimately lead to the successful development of new therapeutic agents. iPSCs also hold great hope for advancing the use of live cells as therapies for correcting the physiological manifestations caused by disease or injury.

Generation and characterization of high-quality, footprint-free human induced pluripotent stem cell lines from 3,000 donors to investigate multigenic diseases

Funding Type: 
hiPSC Derivation
Grant Number: 
ID1-06557
ICOC Funds Committed: 
$16 000 000
Disease Focus: 
Developmental Disorders
Genetic Disorder
Heart Disease
Infectious Disease
Alzheimer's Disease
Neurological Disorders
Autism
Respiratory Disorders
Vision Loss
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
Induced pluripotent stem cells (iPSCs) have the potential to differentiate to nearly any cells of the body, thereby providing a new paradigm for studying normal and aberrant biological networks in nearly all stages of development. Donor-specific iPSCs and differentiated cells made from them can be used for basic and applied research, for developing better disease models, and for regenerative medicine involving novel cell therapies and tissue engineering platforms. When iPSCs are derived from a disease-carrying donor; the iPSC-derived differentiated cells may show the same disease phenotype as the donor, producing a very valuable cell type as a disease model. To facilitate wider access to large numbers of iPSCs in order to develop cures for polygenic diseases, we will use a an episomal reprogramming system to produce 3 well-characterized iPSC lines from each of 3,000 selected donors. These donors may express traits related to Alzheimer’s disease, autism spectrum disorders, autoimmune diseases, cardiovascular diseases, cerebral palsy, diabetes, or respiratory diseases. The footprint-free iPSCs will be derived from donor peripheral blood or skin biopsies. iPSCs made by this method have been thoroughly tested, routinely grown at large scale, and differentiated to produce cardiomyocytes, neurons, hepatocytes, and endothelial cells. The 9,000 iPSC lines developed in this proposal will be made widely available to stem cell researchers studying these often intractable diseases.
Statement of Benefit to California: 
Induced pluripotent stem cells (iPSCs) offer great promise to the large number of Californians suffering from often intractable polygenic diseases such as Alzheimer’s disease, autism spectrum disorders, autoimmune and cardiovascular diseases, diabetes, and respiratory disease. iPSCs can be generated from numerous adult tissues, including blood or skin, in 4–5 weeks and then differentiated to almost any desired terminal cell type. When iPSCs are derived from a disease-carrying donor, the iPSC-derived differentiated cells may show the same disease phenotype as the donor. In these cases, the cells will be useful for understanding disease biology and for screening drug candidates, and California researchers will benefit from access to a large, genetically diverse iPSC bank. The goal of this project is to reprogram 3,000 tissue samples from patients who have been diagnosed with various complex diseases and from healthy controls. These tissue samples will be used to generate fully characterized, high-quality iPSC lines that will be banked and made readily available to researchers for basic and clinical research. These efforts will ultimately lead to better medicines and/or cellular therapies to treat afflicted Californians. As iPSC research progresses to commercial development and clinical applications, more and more California patients will benefit and a substantial number of new jobs will be created in the state.

Tissue Collection for Accelerating iPSC Research in Cardiovascular Diseases

Funding Type: 
Tissue Collection for Disease Modeling
Grant Number: 
IT1-06596
Investigator: 
ICOC Funds Committed: 
$1 435 371
Disease Focus: 
Heart Disease
oldStatus: 
Active
Public Abstract: 
Heart failure is a very common and chronic condition defined by an inability of the heart to pump blood effectively. Over half of cases of heart failure are caused by a condition called dilated cardiomyopathy, which involves dilation of the heart cavity and weakening of the muscle. Importantly, many cases of this disease do not have a known cause and are called “idiopathic” (i.e., physicians do not know why). Over the past 2 decades, doctors and scientists started realizing the disease can cluster in families, leading them to think there is a genetic cause to the disease. This resulted in discovering multiple genes that cause this disease. Nonetheless, the majority of cases of dilated hearts that cluster in families do not have a known genetic cause. Now scientists can turn blood and skin cells into heart cells by genetically manipulating them and creating engineered stem cells called “induced pluripotent stem cells” or iPSCs. This approach enables the scientists to study what chemical or genetic changes are happening to cause the problem. Also because these cells behave similar to the cells in the heart, scientists can now test new medicines on these cells first before trying them in patients. Here we aim to collect tissue from 800 patients without a known cause for their dilated hearts (and 200 control individuals) to help accelerate our understanding of this debilitating disease and hopefully offer new and better treatments.
Statement of Benefit to California: 
Heart failure is a significant health burden in California with rising hospitalization and death rates in the state. We have a very limited understanding of the disease and so far the existing treatments only slow down the disease and the changes that happen rather than target the root cause. By studying a subgroup of the dilated cardiomyopathy patients who have no identified cause, we can work on identifying genetic causes of the disease, some of the biology happening inside the heart cell, and provide new treatments that can prevent the disease from happening or progressing. Improving the outcome of this debilitating disease and providing new treatments will go a long way to helping a large group of Californians lead healthier and longer lives. There are estimates that the US economy loses $10 billion (not counting medical costs), because heart failure patients are unable to work. Hence new knowledge and developments gained from this research can go a long way to ameliorating that cost. Finally, heart failure is the most common chronic disease patients in California are hospitalized for. This research targets over half of those admissions. If this research is able to cut the hospitalization rate even by 1%, this would translate to millions of dollars in savings to the state. Continuing to invest in innovation will make our state a hotbed for the biotechnology industry, which in turn advances the state’s economic and educational status.

Preclinical evaluation of human embryonic stem cell-derived cardiovascular progenitors in a large animal model

Funding Type: 
New Faculty Physician Scientist
Grant Number: 
RN3-06378
ICOC Funds Committed: 
$2 930 388
Disease Focus: 
Heart Disease
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Active
Public Abstract: 
Because the regenerative capacity of adult heart is limited, any substantial cell loss as a result of a heart attack is mostly irreversible and may lead to progressive heart failure. Human pluripotent stem cells can be differentiated to heart cells, but their properties when transplanted into an injured heart remain unresolved. We propose to perform preclinical evaluation for transplantation of pluripotent stem cell-derived cardiac cells into the injured heart of a pig model. However, an important issue that has limited the progress to clinical use is their fate upon transplantation; that is whether they are capable of integrating into their new environment or they will function in isolation at their own pace. As an analogy, the performance of a symphony can go into chaos if one member plays in isolation from all surrounding cues. Therefore, it is important to determine if the transplanted cells can beat in harmony with the rest of the heart and if these cells will provide functional benefit to the injured heart. We plan to isolate cardiac cells derived from human pluripotent stem cells, transplant them into a pig’s injured heart, determine if they result in improvement of the heart function, and perform detailed electrophysiology studies to determine their integration into the host tissue. The success of the proposed project will set the platform for future clinical trails of stem cell therapy for heart disease.
Statement of Benefit to California: 
Heart disease remains the leading cause of mortality and morbidity in the US with an estimated annual cost of over $300 billion. In California alone, more than 70,000 people die every year from cardiovascular diseases. Despite major advancement in treatments for patients with heart failure, which is mainly due to cellular loss upon myocardial injury, the mortality rate remains high. Human embryonic stem cells (hESC) and induced pluripotent stem cells (iPSC) could provide an attractive therapeutic option to treat patients with damaged heart. We propose to isolate heart cells from hESCs and transplant them in an injured pig’s heart and study their fate. In the process, we will develop reagents that can be highly valuable for future research and clinical studies. The reagents generated in these studies can be patented forming an intellectual property portfolio shared by the state and the institution where the research is carried out. Most importantly, the research that is proposed in this application could lead to future stem cell-based therapies that would restore heart function after a heart attack. We expect that California hospitals and health care entities will be first in line for trials and therapies. Thus, California will benefit economically and it will help advance novel medical care.
Progress Report: 
  • Identification and isolation of pure cardiac cells derived from human pluripotent stem cells has proven to be a difficult task. We have designed a method to genetically engineer human embryonic stem cells (hESCs) to harbor a label that is expressed during sequential maturation of cardiac cells. This will allow us to prospectively isolate cardiac cells at different stages of development for further characterization and transplantation. Using this method, we have screened proteins that are expressed on the surface of cells as markers. Using antibodies against these surface markers allows for isolation of these cells using cell sorting techniques. Thus far, we have identified two surface markers that can be used to isolate early cardiac progenitors. Using these markers, we have enriched for cardiac cells from differentiating hESCs and have characterized their properties in the dish as well as in small animals. We plan to transplant these cells in large animal models and monitor their survival, expansion and their integration into the host myocardium. Molecular imaging techniques are used to track these cells upon transplantation.

Human Induced Pluripotent Stem Cell-Derived Cardiovascular Progenitor Cells for Cardiac Cell Therapy.

Funding Type: 
New Faculty Physician Scientist
Grant Number: 
RN3-06455
ICOC Funds Committed: 
$3 179 315
Disease Focus: 
Heart Disease
Stem Cell Use: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
Despite therapeutic advances, cardiovascular disease remains a leading cause of mortality and morbidity in California. Regenerative therapies that restore normal function after a heart attack would have an enormous societal and financial impact. Although very promising, regenerative cardiac cell therapy faces a number of challenges and technological hurdles. Human induced pluripotent stem cells (hiPSC) allow the potential to deliver patient specific, well-defined cardiac progenitor cells (CPC) for regenerative clinical therapies. We propose to translate recent advances in our lab into the development of a novel, well-defined hiPSC-derived CPC therapy. All protocols will be based on clinical-grade, FDA-approvable, animal product-free methods to facilitate preclinical testing in a large animal model. This application will attempt to translate these findings by: -Developing techniques and protocols utilizing human induced pluripotent stem cell-derived cardiac progenitor cells at yields adequate to conduct preclinical large animal studies. -Validation of therapeutic activity will be in small and large animal models of ischemic heart disease by demonstrating effectiveness of hiPSC-derived CPCs in regenerating damaged myocardium post myocardial infarction in small and large animal models. This developmental candidate and techniques described here, if shown to be a feasible alternative to current approaches, would offer a novel approach to the treatment of ischemic heart disease.
Statement of Benefit to California: 
Cardiovascular disease remains the leading cause of morbidity and mortality in California and the US costing the healthcare system greater than 300 billion dollars a year. Although current therapies slow progression of heart disease, there are few options to reverse or repair the damaged heart. The limited ability of the heart to regenerate following a heart attack results in loss of function and heart failure. Human clinical trials testing the efficacy of adult stem cell therapy to restore mechanical function after a heart attack, although promising, have had variable results with modest improvements. The discovery of human induced pluripotent stem cells offers a potentially unlimited renewable source for patient specific cardiac progenitor cells. However, practical application of pluripotent stem cells or their derivatives face a number of challenges and technological hurdles. We have demonstrated that cardiac progenitor cells, which are capable of differentiating into all cardiovascular cell types, are present during normal fetal development and can be isolated from human induced pluripotent stem cells. We propose to translate these findings into a large animal pre-clinical model and eventually to human clinical trials. This could lead to new therapies that would restore heart function after a heart attack preventing heart failure and death. This will have tremendous societal and financial benefits to patients in California and the US in treating heart failure.
Progress Report: 
  • Cardiovascular disease remains to be a major cause of morbidity and mortality in California and the United States. Despite the best medical therapies, none address the issue of irreversible myocardial tissue loss after a heart attack and thus there has been a great interest to develop approaches to induce regeneration. Our lab has focused on harvesting the full potential of patient specific induced pluripotent stem cells (iPSCs) to use to attempt to regenerate the damaged tissue. We believe that these iPSCs can be potentially used in the future to generate sufficient number of cells to be implanted in the damaged heart to regenerate the lost tissue post heart attack. Our lab has studied how these cardiac progenitors evolve in the developing heart and applied our finding to iPSCs to recapitulate the cardiac progenitors to ultimately use in clinical therapies. We have successfully derived these cardiac progenitors from patient derived iPSCs in a clinical grade fashion to ensure that we can apply same protocols in the future to clinical use if we are successful in demonstrating the efficacy of this therapy in our translational large animal studies that we will be conducting.

Mechanism of heart regeneration by cardiosphere-derived cells

Funding Type: 
Basic Biology IV
Grant Number: 
RB4-06215
ICOC Funds Committed: 
$1 367 604
Disease Focus: 
Heart Disease
Stem Cell Use: 
Adult Stem Cell
oldStatus: 
Active
Public Abstract: 
In the process of a heart attack, clots form suddenly on top of cholesterol-laden plaques, blocking blood flow to heart muscle. As a result, living heart tissue dies and is replaced by scar. The larger the scar, the higher the chance of premature death and disability following the heart attack. While conventional treatments aim to limit the initial injury (by promptly opening the clogged artery) and to prevent further damage (using various drugs), regenerative therapy for heart attacks seeks to regrow healthy heart muscle and to dissolve scar. To date, cell therapy with CDCs is the only intervention which has been shown to be clinically effective in regenerating the injured human heart (in Dr. Marbán’s CADUCEUS trial). However, the cellular origin of the newly-formed heart muscle and the mechanisms underlying its generation remain unknown. The present grant seeks to understand those basic mechanisms in detail, relying upon state-of-the-art scientific methods and preclinical disease models. Our work to date suggests that much of the benefit is due to an indirect effect of transplanted CDCs to stimulate the proliferation of surrounding host heart cells. This represents a major, previously-unrecognized mechanism of cardiac regeneration in response to cell therapy. The proposed project will open up novel mechanistic insights which will hopefully enable us to boost the efficacy of stem cell-based treatments by bolstering the regeneration of injured heart muscle.
Statement of Benefit to California: 
Coronary artery disease is the predominant cause of premature death and disability in California. Clots form suddenly on top of cholesterol-laden plaques in the wall of a coronary artery, blocking blood flow to the heart muscle. This leads to a “heart attack”, in which living heart muscle dies and is replaced by scar. The larger the scar, the greater the chance of death and disability following the heart attack. While conventional treatments aim to limit the initial injury (by promptly opening the clogged artery) and to prevent further injury (using various drugs), regenerative therapy for heart attacks seeks to regrow healthy heart muscle and to dissolve scar. To date, cell therapy with CDCs is the only intervention that has been shown to be clinically effective in regenerating the injured human heart (in Dr. Marbán’s CADUCEUS trial, recently spotlighted by CIRM; see http://www.cirm.ca.gov/Video/stem-cell-clinical-trial-heart-failure-eduardo-marb%C3%A1n-cirm-spotlight-disease). However, the cellular origin of the newly-formed heart muscle and the mechanisms underlying its generation remain unknown. The present grant seeks to understand those basic mechanisms in detail, relying upon state-of-the-art scientific methods and preclinical disease models. The resulting insights will enable more rational development of novel therapeutic approaches, to the benefit of the public health of the citizens of California. Economic benefits may also accrue from licensing of new technology.
Progress Report: 
  • Key abbreviations:
  • CDCs: cardiosphere-derived cells
  • MI: myocardial infarction
  • The present award tests the hypothesis that CDCs promote regrowth of normal mammalian heart tissue through induction of adult cardiomyocyte cell cycle re-entry and proliferation (as occurs naturally in zebrafish and neonatal mice). Such a mechanism, if established, would challenge the dogma that terminally-differentiated adult cardiomyocytes cannot re-enter the cell cycle. We have employed an inducible cardiomyocyte-specific fate-mapping approach (to specifically mark resident myocytes and their progeny), coupled with novel methods of myocyte purification and rigorous quantification. We have also developed assays that enable us to exclude potential technical confounding factors. The use of bitransgenic mice is essential for our experimental design (as it enables fate mapping of resident myocytes in a mammalian model), while the use of mouse CDCs in our in vivo experiments (as opposed to human CDCs) enables us to avoid immunosuppression and its complications. To date, mouse, rat and pig models have proven to be reliable in predicting clinical effects of CDC therapy in humans, and results with human and mouse CDCs in comparable models (e.g., SCID mice for human CDCs versus wild-type mice for mouse CDCs) have not revealed any major mechanistic divergence. Our results demonstrate that induction of cardiomyocyte proliferation represents a major, previously-unrecognized mechanism of cardiac regeneration in response to cell therapy. One full-length publication describing these findings has appeared (K. Malliaras et al., EMBO Mol Med, 2013, 5:191-209), and another paper has been submitted. The work has already begun to open up novel mechanistic insights which will enable us to improve the efficacy of stem cell-based treatments and bolster cardiomyocyte repopulation of infarcted myocardium.

A new paradigm of lineage-specific reprogramming

Funding Type: 
Basic Biology IV
Grant Number: 
RB4-06035
ICOC Funds Committed: 
$1 708 560
Disease Focus: 
Heart Disease
Stem Cell Use: 
Directly Reprogrammed Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
Recently, we devised and reported a new regenerative medicine paradigm that entails temporal/transient overexpression of induced pluripotent stem cell based reprogramming factors in skin cells, leading to the rapid generation of “activated” cells, which can then be directed by specific growth factors and small molecules to “relax” back into various defined and homogenous tissue-specific precursor cell types (including nervous cells, heart cells, blood vessel cells, and pancreas and liver progenitor cells), which can be expanded and further differentiated into mature cells entirely distinct from fibroblasts. In this proposal, combined with small molecules that can functionally replace reprogramming transcription factors as well as substantially improve reprogramming efficiency and kinetics, we aim to further develop and mechanistically characterize chemically defined, non-integrating approaches (e.g., mRNA, miRNA, episomal plasmids and/or small molecule-based) to robustly and efficiently reprogram skin fibroblast cells into expandable heart precursor cells. Specifically, we will: determine if we can use non-integrating methods to destabilize human fibroblasts and facilitate their direct reprogramming into the heart precursor cells; characterize of heart cells generated by the direct programming methods, both in the tissue culture dish and in a mouse model of heart attack; and characterize newly identified reprogramming enhancing small molecules mechanistically.
Statement of Benefit to California: 
This study will develop and mechanistically characterize a new method of generating safe patient specific heart cells that could be useful in treating heart failure which afflicts millions of Californians and accounts for billions of dollars in healthcare spending annually. Additionally, the small molecules discovered in this study could be good candidates for future drug development as well as being broadly useful for other regenerative medicine applications. These advances could also be a platform for new personalized medicine/ cell banking businesses which could bring economic growth in addition to improving the health of Californians.
Progress Report: 
  • During the reporting period, we have made very significant progress toward the following research aims: (1) Using the Oct4-based reprogramming assay system established, we were able to screen for and identify small molecules that can replace the other three genes in the Cell-Activation and Signaling-Directed (CASD) lineage conversion paradigm for reprogramming fibroblasts into cardiac lineage. (2) Using in-depth assays, we have examined the process using lineage-tracing methods and characterized those Oct4/small molecules-reprogrammed cardiac cells in vitro. (3) Most importantly, we were able to identify a baseline condition that appears to reprogram human fibroblasts into cardiac cells using defined conditions.

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