Tailoring Cardiac Synthetic Transcriptional Modulation Towards Precision Medicine

Molecular and genetic differences between individual cells within tissues underlie cellular heterogeneities defining organ physiology and function in homeostasis as well as in disease states. Transcriptional control of endogenous gene expression has been intensively studied for decades. Thanks to a fast-developing field of single cell genomics, we are facing an unprecedented leap in information available pertaining organ biology offering a comprehensive overview. The single-cell technologies that arose aided in resolving the precise cellular composition of many organ systems in the past years. Importantly, when applied to diseased tissues, the novel approaches have been immensely improving our understanding of the underlying pathophysiology of common human diseases. With this information, precise prediction of regulatory elements controlling gene expression upon perturbations in a given cell type or a specific context will be realistic. Simultaneously, the technological advances in CRISPR-mediated regulation of gene transcription as well as their application in the context of epigenome modulation, have opened up novel avenues for targeted therapy and personalized medicine. Here, we discuss the fast-paced advancements during the recent years and the applications thereof in the context of cardiac biology and common cardiac disease. The combination of single cell technologies and the deep knowledge of fundamental biology of the diseased heart together with the CRISPR-mediated modulation of gene regulatory networks will be instrumental in tailoring the right strategies for personalized and precision medicine in the near future. In this review, we provide a brief overview of how single cell transcriptomics has advanced our knowledge and paved the way for emerging CRISPR/Cas9-technologies in clinical applications in cardiac biomedicine.

Microglia Heterogeneity in Alzheimer’s Disease: Insights From Single-Cell Technologies

Microglia are resident immune cells in the central nervous system and play critical roles in brain immunity, development, and homeostasis. The pathology of Alzheimer’s disease (AD) triggers activation of microglia. Microglia express many AD risk genes, suggesting that their response to AD pathology can affect disease progression. Microglia have long been considered a homogenous cell population. The diversity of microglia has gained great interest in recent years due to the emergence of novel single-cell technologies, such as single-cell/nucleus RNA sequencing and single-cell mass cytometry by time-of-flight. This review summarizes the current knowledge about the diversity/heterogeneity of microglia and distinct microglia states in the brain of both AD mouse models and patients, as revealed by single-cell technologies. It also discusses the future developments for application of single-cell technologies and the integration of these technologies with functional studies to further dissect microglia biology in AD. Defining the functional correlates of distinct microglia states will shed new light on the pathological roles of microglia and might uncover new relevant therapeutic targets for AD.

Perspectives on Challenges to Cell Therapy Development in Taiwan: Strengthening Evidential Standards and Ways Forward

Over the past years, the field of regenerative medicine and cell therapy has garnered much interest, extending beyond the bench to broader use, and commercialization. These therapies undergo stringent regulatory oversight as a result of their complexities and potential risk across different jurisdictions. Taiwan’s government, with the aim of developing the country as a hub for regenerative medicine in Asia, enacted a dual track act to promote the development of regenerative and cell therapy products. This qualitative study used purposive sampling to recruit sixteen experts (Twelve respondents from medical institutions and four respondents from the industry) to understand their perspectives on one of the regulatory tracks which governs the medical use of cell technologies and challenges regarding its implementation. Semi-structured interviews were conducted, transcribed, coded and thematically analyzed. Three major themes emerged from the analysis: 1) Perceptions of the “Special Regulation for Cell Therapy” 2) Emerging issues and controversies on the medical use of cell technologies in private clinics, and 3) Challenges impeding the clinical innovation of cell technologies. As reported by the experts, it was clear that the special regulation for cell therapy was aimed at legalizing the clinical use of cell therapy in a similar fashion to an evidence-based pathway, to promote clinical innovation, ensure manufacturing consistency, and improve oversight on cell-based therapies. Thus, the regulation addresses the issues of safety concerns, patient’s access and stem cell tourism. However, the limited approved cell techniques, quality control during cell processing, time, and criteria used in evaluating applications in addition to the need to develop evidential standards for clinical evidence are some of the difficulties faced. Thus, policy interventions on funding, educational resources, training, and regulatory clarity addressing these challenges may positively impact clinical innovation of cell therapy in Taiwan.

sciCAN: Single-cell chromatin accessibility and gene expression data integration via Cycle-consistent Adversarial Network

The booming single-cell technologies bring a surge of high dimensional data that come from different sources and represent cellular systems from different views. With advances in single-cell technologies, integrating single-cell data across modalities arises as a new computational challenge and gains more and more attention within the community. Here, we present a novel adversarial approach, sciCAN, to integrate single-cell chromatin accessibility and gene expression data in an unsupervised manner. We benchmarked sciCAN with 3 state-of-the-art (SOTA) methods in 5 scATAC-seq/scRNA-seq datasets, and we demonstrated that our method dealt with data integration with better balance of mutual transferring between modalities than the other 3 SOTA methods. We further applied sciCAN to 10X Multiome data and confirmed the integrated representation preserves information of the hematopoietic hierarchy. Finally, we investigated CRSIPR-perturbed single-cell K562 ATAC-seq and RNA-seq data to identify cells with related responses to different perturbations in these different modalities.