Background: Cardiac regeneration after injury is limited by the low proliferative capacity of adult mammalian cardiomyocytes (CMs). However, certain animals readily regenerate lost myocardium through a process involving dedifferentiation, which unlocks their proliferative capacities. Methods: We bred mice with inducible, CM-specific expression of the Yamanaka factors, enabling adult CM reprogramming and dedifferentiation in vivo. Results: Two days after induction, adult CMs presented a dedifferentiated phenotype and increased proliferation in vivo. Microarray analysis revealed that upregulation of ketogenesis was central to this process. Adeno-associated virus-driven HMGCS2 overexpression induced ketogenesis in adult CMs and recapitulated CM dedifferentiation and proliferation observed during partial reprogramming. This same phenomenon was found to occur after myocardial infarction, specifically in the border zone tissue, and HMGCS2 knockout mice showed impaired cardiac function and response to injury. Finally, we showed that exogenous HMGCS2 rescues cardiac function after ischemic injury. Conclusions: Our data demonstrate the importance of HMGCS2-induced ketogenesis as a means to regulate metabolic response to CM injury, thus allowing cell dedifferentiation and proliferation as a regenerative response.

The advent of induced pluripotent stem cells (iPSCs) has advanced our understanding of the molecular mechanisms of human disease, drug discovery, and regenerative medicine. As such, the use of iPSCs in drug development and validation has shown a sharp increase in the past 15 years. Furthermore, many labs have been successful in reproducing many disease phenotypes, often difficult or impossible to capture, in commonly used cell lines or animal models. However, there still remain limitations such as the variability between iPSC lines as well as their maturity. Here, we aim to discuss the strategies in generating iPSC-derived cardiomyocytes and neurons for use in disease modeling, drug development and their use in cell therapy.

Since December 2019, the novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected ~435 million people and caused ~6 million related deaths as of March 2022. To combat COVID-19, there have been many attempts to repurpose FDA-approved drugs or revive old drugs. However, many of the current treatment options have been known to cause adverse drug reactions. We employed a population-based drug screening platform using 13 human leukocyte antigen (HLA) homozygous human induced pluripotent cell (iPSC) lines to assess the cardiotoxicity and neurotoxicity of the first line of anti-COVID-19 drugs. We also infected iPSC-derived cells to understand the viral infection of cardiomyocytes and neurons. We found that iPSC-derived cardiomyocytes express the ACE2 receptor which correlated with a higher infection of the SARS-CoV-2 virus (r = 0.86). However, we were unable to detect ACE2 expression in neurons which correlated with a low infection rate. We then assessed the toxicity of anti-COVID-19 drugs and identified two cardiotoxic compounds (remdesivir and arbidol) and four neurotoxic compounds (arbidol, remdesivir, hydroxychloroquine, and chloroquine). These data show that this platform can quickly and easily be employed to further our understanding of cell-specific infection and identify drug toxicity of potential treatment options helping clinicians better decide on treatment options.

Heart Failure (HF) impacts approximately 64 million people globally. While overall incidence of HF is relatively stable across countries, the overall number of HF patients is increasing due to aging populations. Many articles examine the microbiome in HF, however, studies from humans have not been analyzed systematically. The aim of this meta-analysis is to bridge this gap by analyzing previously published data on human HF patients with untargeted metabolomics to understand whether microbially-mediated metabolites are consistently important for HF status. A systematic survey of the literature identified 708 articles discussing HF, the microbiome, and metabolomics. Of these, 82 were primary studies of HF patients, 61 studied human adults, 23 included an untargeted metabolomics measure, and 3 studies had data that was usable and publicly accessible. These studies include a GCMS study from stool, NMR of saliva and exhaled breath condensate, and LCMS from left ventricle of HF patients undergoing transplantation and unused donor hearts. Significant differences were observed from PCA between HF and controls for stool and left ventricle, but not saliva or EBC samples. OPLS-DA was conducted for stool and ventricle samples, and further revealed significant group differences. Univariate testing with FDR correction revealed 8 significant microbially-relevant metabolites (p < 0.005 after correction), most notably asparagine from left ventricle and 2-methylbutyryl carnitine from stool. Though there is much discussion of the microbiome in health outcomes in HF, there is limited research from human populations. Some microbial co-metabolites from both stool and heart were significantly associated with HF.