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The heart is unable to regenerate cardiac muscle lost from heart attacks or injury. An advance that could significantly reduce the burden of chronic illness and death from cardiovascular disease would be to regrow damaged heart muscle, thus restoring the organ to pre injury heart function.
Dr. Reza Ardehali, a UCLA associate professor of medicine (cardiology), heads a group of researchers exploring novel therapies to deliver stem cell-derived heart cells to replace scars formed after a heart attack.
Dr. Ardehali’s lab uses multiple approaches for developing stem cell therapies. Their lab uses clonal analysis to determine the proliferative capacity of cardiac cells during development and after injury. This informs the investigators on the 1) cell types responsible for proliferation during development, 2) the extent of cellular expansion during development, and 3) the time period that governs the proliferative characteristics of precursor cells in the heart. These approaches and hypotheses are then tested in genetically modified mice, lineage tracing and fate mapping, and mathematical models.
Cell fate mapping in the heart (Image courtesy of Ardehali Lab)
Dr. Reza Ardehali
The lab also use pluripotent stem cell for cardiac regenerative therapies. The lab identifies novel surface markers for purification of pluripotent stem cell (PCS)-derived cardiovascular progenitors (CVPs). The lab seeks to identify surface markers that can be used to prospectively isolate progenitors capable of engraftment into the injured heart and for translational application of PSC-derived cardiovascular progenitors for regenerative purposes. Using a variety of invasive and non-invasive imaging modalities, the lab is investigating the potential electromechanical integration of PSC-derived cardiac cells into the injured hearts of large animals. The long-term goal is to utilize the preclinical data obtained in these studies for future clinical trials of PSC-derived CVPs to treat heart disease.
The Ardehali lab also studies the developmental origin of cardiac fibroblasts using transgenic mouse models to identify the developmental origins of cardiac fibroblasts. In addition, the lab is interested in determining whether the heterogeneity of cardiac fibroblasts has a role in differential response to cardiac injury. The lab is exploring the role of perivascular cells in cardiac fibrosis.
Dr. Ardehali and his team are actively working to make his vision a reality. His collaborators include UCLA stem cell biologists, cardiologists, bioengineers, developmental biologists and cardiac surgeons, among others.
The heart does not possess a robust ability to regenerate and heals by scar formation. Multiple studies have demonstrated that the amount of scar tissue in the heart is an independent predictor of morbidity and mortality. Scar tissue reduces cvardiac function induces the formation of more scar tissue and leads to cardiac arrhythmias and sudden death.
The laboratory of Arjun Deb is devoted to the study of the biology of scar and how scarring can be modulated therapeutically. The spatio-temporal mechanisms regulating scarring are conserved across many organs and “thus the hope is if one can alter scarring in one organ, the therapeutic principles can be applied to other organs” as well says Dr Arjun Deb, the director of the UCLA cardiovascular theme.
Dr. Arjun Deb
Reversing scarring, or preventing it in the first place, has been one of the major challenges of cardiovascular research, says Dr. Arjun Deb, a professor of medicine (cardiology) and senior author of a UCLA study published in 2014 in Nature. Their group was the first to show that cells in scar tissue retained cellular plasticity for a brief time window and could be manipulated to change the amount of scarring.
More recently, the Deb lab has demonstrated that scars have an inherent ability to control their own size (Yokota et al. Cell 2020). The lab showed that type V collagen , a minor constituent of scar tissue regulated the mechanical properties of the scar tissue and mechanosensitive receptors on fibroblasts sensed changes in mechanical properties of scar tissue to determine the volume of scar to be formed. The lab used small molecules to interfered with such feedback mechanisms and showed scar size could be altered in this manner to therapeutic advantage.
Dr. Tom Vondriska
The Vondriska laboratory studies the biology of chromatin and how chromatin reorganization occurs in heart failure. In recent years, the lab has carried out the first chromatin conformation capture experiments in the heart, determining the endogenous organization of the genome in cardiac myocytes. With this blueprint, the lab is answering the following questions: How do transcription neighborhoods form? What is the role of inter-chromosomal interactions and other nuclear features in genomic architecture? How do features of local accessibility relate to local and global architecture?
The lab is determining the structural features required for disease-associated gene expression and investigating how global chromatin accessibility is altered during cardiovascular disease. These studies are targeted to identify diagnostic features of the epigenome that indicate the progression or reversion of disease and to develop strategies to remodel chromatin therapeutically.
The Packard lab studies the biology of atherosclerosis and heart failure with particular emphasis in understanding how chemotherapeutic drugs exert toxic effects on the heart.
The lab integrates molecular and cellular techniques to dissect mechanisms of chemotherapy induced cardiotoxicity as well as designs novel imaging techniques to visualize myocyte contraction in real time. The Packard lab has created a new imaging technology (DIAMOND) that can determine segmental abnormalities in cardiac contraction following administration of chemotherapeutic agents.
The Umar Laboratory’s research is focused on investigating the molecular mechanisms and pathophysiology of primary and secondary forms of pulmonary hypertension and associated right ventricular dysfunction. The lab’s long-term goal is to devise novel regenerative therapies for these cardiopulmonary disorders. They are also interested in investigating novel strategies for perioperative cardiopulmonary organ protection.
Pulmonary hypertension is a chronic pulmonary vascular disease without a definitive cure.
The Umar lab is using state-of-the-art in vivo mouse and rat models, in vitro cell culture systems, and human blood and tissue samples to investigate the molecular mechanisms of the development of primary and secondary pulmonary hypertension. The lab is also investigating adverse structural and electrical remodeling of the right ventricle secondary to pressure overload that often leads to arrhythmias and sudden cardiac death.