Dr. Mercola is Professor of Medicine and Professor in the Stanford Cardiovascular Institute. He completed postdoctoral training at the Dana-Farber Cancer Institute and Harvard Medical School, was on the faculty in the Department of Cell Biology at Harvard Medical School for 12 years, and later at the Sanford-Burnham-Prebys Institute and Department of Bioengineering at the University of California, San Diego before relocating to Stanford in 2015.
Prof. Mercola is known for identifying many of the factors that are responsible for inducing and forming the heart, including the discovery that Wnt inhibition is a critical step in cardiogenesis that provided the conceptual basis and reagents for the large-scale production of cardiovascular tissues from pluripotent stem cells. He has collaborated with medicinal chemists, optical engineers and software developers to pioneer the use of patient iPSC-cardiomyocytes for disease modeling, safety pharmacology and drug development. His academic research is focused on developing and using quantitative assays of patient-specific cardiomyocyte function to discover druggable targets for preserving contractile function in heart failure and promoting regeneration following ischemic injury. He co-established drug screening and assay development at the Conrad Prebys Drug Discovery Center (San Diego), which operated as one of 4 large screening centers of the US National Institutes of Health (NIH) Molecular Libraries screening initiative and continues as one of the largest academic drug screening centers.
Prof. Mercola received an NIH MERIT award for his work on heart formation, and authored over 120 papers. He holds numerous patents, including describing the invention of the first engineered dominant negative protein and small molecules for stem cell and cancer applications. He serves on multiple editorial and advisory boards, including Vala Sciences, Stem Cell Theranostics, Regencor, and the Human Biomolecular Research Institute. His laboratory is funded by the NIH, California Institute for Regenerative Medicine and the Fondation Leducq.
- The All-Chemical Approach: A Solution for Converting Fibroblasts Into Myocytes. Circulation research 2016; 119 (4): 505-507
High throughput physiological screening of iPSC-derived cardiomyocytes for drug development
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
2016; 1863 (7): 1717-1727
Cardiac drug discovery is hampered by the reliance on non-human animal and cellular models with inadequate throughput and physiological fidelity to accurately identify new targets and test novel therapeutic strategies. Similarly, adverse drug effects on the heart are challenging to model, contributing to costly failure of drugs during development and even after market launch. Human induced pluripotent stem cell derived cardiac tissue represents a potentially powerful means to model aspects of heart physiology relevant to disease and adverse drug effects, providing both the human context and throughput needed to improve the efficiency of drug development. Here we review emerging technologies for high throughput measurements of cardiomyocyte physiology, and comment on the promises and challenges of using iPSC-derived cardiomyocytes to model disease and introduce the human context into early stages of drug discovery. This article is part of a Special Issue entitled: Cardiomyocyte biology: Integration of Developmental and Environmental Cues in the Heart edited by Marcus Schaub and Hughes Abriel.
View details for DOI 10.1016/j.bbamcr.2016.03.003
View details for Web of Science ID 000378360400004
View details for PubMedID 26952934
Notch-independent RBPJ controls angiogenesis in the adult heart
Increasing angiogenesis has long been considered a therapeutic target for improving heart function after injury such as acute myocardial infarction. However, gene, protein and cell therapies to increase microvascularization have not been successful, most likely because the studies failed to achieve regulated and concerted expression of pro-angiogenic and angiostatic factors needed to produce functional microvasculature. Here, we report that the transcription factor RBPJ is a homoeostatic repressor of multiple pro-angiogenic and angiostatic factor genes in cardiomyocytes. RBPJ controls angiogenic factor gene expression independently of Notch by antagonizing the activity of hypoxia-inducible factors (HIFs). In contrast to previous strategies, the cardiomyocyte-specific deletion of Rbpj increased microvascularization of the heart without adversely affecting cardiac structure or function even into old age. Furthermore, the loss of RBPJ in cardiomyocytes increased hypoxia tolerance, improved heart function and decreased pathological remodelling after myocardial infarction, suggesting that inhibiting RBPJ might be therapeutic for ischaemic injury.
View details for DOI 10.1038/ncomms12088
View details for Web of Science ID 000379113200001
View details for PubMedID 27357444
Epicardial FSTL1 reconstitution regenerates the adult mammalian heart.
2015; 525 (7570): 479-485
The elucidation of factors that activate the regeneration of the adult mammalian heart is of major scientific and therapeutic importance. Here we found that epicardial cells contain a potent cardiogenic activity identified as follistatin-like 1 (Fstl1). Epicardial Fstl1 declines following myocardial infarction and is replaced by myocardial expression. Myocardial Fstl1 does not promote regeneration, either basally or upon transgenic overexpression. Application of the human Fstl1 protein (FSTL1) via an epicardial patch stimulates cell cycle entry and division of pre-existing cardiomyocytes, improving cardiac function and survival in mouse and swine models of myocardial infarction. The data suggest that the loss of epicardial FSTL1 is a maladaptive response to injury, and that its restoration would be an effective way to reverse myocardial death and remodelling following myocardial infarction in humans.
View details for DOI 10.1038/nature15372
View details for PubMedID 26375005
- Epicardial FSTL1 reconstitution regenerates the adult mammalian heart NATURE 2015; 525 (7570): 479-?
Developmental origin of age-related coronary artery disease
2015; 107 (2): 287-294
Age and injury cause structural and functional changes in coronary artery smooth muscle cells (caSMCs) that influence the pathogenesis of coronary artery disease. Although paracrine signalling is widely believed to drive phenotypic changes in caSMCs, here we show that developmental origin within the fetal epicardium can have a profound effect as well.Fluorescent dye and transgene pulse-labelling techniques in mice revealed that the majority of caSMCs are derived from Wt1(+), Gata5-Cre(+) cells that migrate before E12.5, whereas a minority of cells are derived from a later-emigrating, Wt1(+), Gata5-Cre(-) population. We functionally evaluated the influence of early emigrating cells on coronary artery development and disease by Gata5-Cre excision of Rbpj, which prevents their contribution to coronary artery smooth muscle cells. Ablation of the Gata5-Cre(+) population resulted in coronary arteries consisting solely of Gata5-Cre(-) caSMCs. These coronary arteries appeared normal into early adulthood; however, by 5-8 months of age, they became progressively fibrotic, lost the adventitial outer elastin layer, were dysfunctional and leaky, and animals showed early mortality.Taken together, these data reveal heterogeneity in the fetal epicardium that is linked to coronary artery integrity, and that distortion of the coronaries epicardial origin predisposes to adult onset disease.
View details for DOI 10.1093/cvr/cvv167
View details for Web of Science ID 000359318200011
APJ acts as a dual receptor in cardiac hypertrophy
2012; 488 (7411): 394-398
Cardiac hypertrophy is initiated as an adaptive response to sustained overload but progresses pathologically as heart failure ensues. Here we report that genetic loss of APJ, a G-protein-coupled receptor, confers resistance to chronic pressure overload by markedly reducing myocardial hypertrophy and heart failure. In contrast, mice lacking apelin (the endogenous APJ ligand) remain sensitive, suggesting an apelin-independent function of APJ. Freshly isolated APJ-null cardiomyocytes exhibit an attenuated response to stretch, indicating that APJ is a mechanosensor. Activation of APJ by stretch increases cardiomyocyte cell size and induces molecular markers of hypertrophy. Whereas apelin stimulates APJ to activate G?i and elicits a protective response, stretch signals in an APJ-dependent, G-protein-independent fashion to induce hypertrophy. Stretch-mediated hypertrophy is prevented by knockdown of ?-arrestins or by pharmacological doses of apelin acting through G?i. Taken together, our data indicate that APJ is a bifunctional receptor for both mechanical stretch and the endogenous peptide apelin. By sensing the balance between these stimuli, APJ occupies a pivotal point linking sustained overload to cardiomyocyte hypertrophy.
View details for DOI 10.1038/nature11263
View details for Web of Science ID 000307501000045
View details for PubMedID 22810587
Cardiac muscle regeneration: lessons from development
GENES & DEVELOPMENT
2011; 25 (4): 299-309
The adult human heart is an ideal target for regenerative intervention since it does not functionally restore itself after injury yet has a modest regenerative capacity that could be enhanced by innovative therapies. Adult cardiac cells with regenerative potential share gene expression signatures with early fetal progenitors that give rise to multiple cardiac cell types, suggesting that the evolutionarily conserved regulatory networks that drive embryonic heart development might also control aspects of regeneration. Here we discuss commonalities of development and regeneration, and the application of the rich developmental biology heritage to achieve therapeutic regeneration of the human heart.
View details for DOI 10.1101/gad.2018411
View details for Web of Science ID 000287365000003
View details for PubMedID 21325131