Professor Qingzhong Xiao

• Vascular stem cell biology and differentiation
• Pluripotent stem cells (ESCs, embryonic stem cells; iPSCs, induced pluripotent stem cells)
• Vascular biology and diseases (Atherosclerosis; Post-angioplasty restenosis or In-stent restenosis; Aortic aneurysm and dissection; Vascular calcification; Transplant atherosclerosis; etc.)
• Cardiac diseases (Heart failure with preserved ejection fraction; Myocardial infarction; Myocardial ischemia-reperfusion (I/R) injury; etc.)
• Cardiovascular regenerative medicine
• Stem cell-derived vascular and cardiac organoids (human iPSCs)

1. Unravelling novel molecular mechanisms underlying cardiovascular cell differentiation from stem/progenitor cells, and exploring their functional implications and therapeutic potential in cardiovascular diseases (CVD).
One of my main research interest is specifically focused on the study of identifying novel targets and signalling pathways such as microRNAs, transcription factors and other molecules which are crucial for vascular endothelial cell (EC) and smooth muscle cell (SMC) differentiation from murine/human pluripotent stem cells as well as adult stem/progenitor cells. By establishing simple but efficient vascular cell differentiation models, I was the first to report that matrix protein Collagen-IV, Nox4, Nrf3, Pla2g7, HDAC3, HDAC7, Cbx3, hnRNPA1, hnRNPA2B1, microRNA-34a, and miR-22 play a key regulatory role in vascular cell differentiation and vascular development (Figure 1). My goal is to continue exploring the key signal pathways underlying cardiovascular cell differentiation and cardiovascular development and their implications in cardiovascular diseases. Such findings will provide useful mechanistic insights into stem cell differentiation towards cardiovascular cells and will significantly enhance the knowledge of stem cell biology and cardiovascular biology in key areas of stem cell self-renewal, vasculogenesis, angiogenesis, and cardiovascular repair.

2. Uncovering the contributions of stem/progenitor cells (SPCs) to cardiovascular diseases (CVD).
Atherosclerosis is the underlying cause of CVDs with growing evidence indicating that SPCs play a pivotal role in the development of atherosclerosis and other CVDs. My group’s ongoing aims is to study the contribution of multiple SPCs to the pathogenesis of CVDs. Using the combination of animal models, human tissue samples, single cell RNA sequencing (scRNA-seq) analysis and cellular lineage in vivo tracing, we aim to uncover the novel mechanisms underlying SPC cell fate decision in the context of CVD pathogenesis and investigate potential uses of stem cell therapy for vascular disease.

3. Identifying and exploring the potential novel therapeutic targets for cardiovascular diseases.
Despite major advances over the past decade, CVD is still the most common cause of death worldwide. Accumulating evidence indicates that different proteases such as matrix metalloproteinases (MMPs) and neutrophil elastase (NE) play an important and distinct role in the development of atherosclerotic lesions and atheromatous plaque rupture. However, their functional role and underlying molecular mechanism remains incompletely understood. One of the key focus of my group is the investigation into the therapeutic potential of MMP8 and NE in various CVDs and elucidating its associated molecular mechanisms (Figure 2). Moreover, by using animal models of CVDs, we were able to confirm dysregulation of key vascular development genes/molecules (e.g. miR-34a, miR-22, Nrf3, and hnRNPA1) identified from our aforementioned stem cell differentiation studies represent potential novel therapeutic candidates for CVDs. Moving forward, we aim to utilise similar strategies to continue identifying and exploring additional novel therapeutic targets for CVDs.

4. Functional involvements of Non-coding RNAs in stem cell fate decision and vascular diseases.
Recently, growing evidence has suggested that non-coding RNAs including microRNAs, long non-coding RNAs, and circular RNAs play crucial roles in embryonic development and various diseases. I aim to explore the significance of these molecules in stem cell pluripotency and vascular cell specifications in addition to their application in preventing vascular diseases.

5. Cellular reprogramming and cardiovascular regeneration.
Cellular reprogramming of somatic cells into pluripotent stem cells or other somatic cells has opened the new avenues of biomedical research and regenerative medicine. Endothelium dysfunction or damage is a hallmark of the onset of vascular diseases. Cell therapy strategies that aim to rapidly repair and restore vascular function are being increasingly explored as viable therapeutic avenues. Development of efficient and robust new methodologies that produce well-characterised, homogenous, clinical-grade cells suitable for tissue repair/re-modelling will have great utility. By using molecules discovered by my group’s early stem cell studies I aim to investigate their potential utility in reprogramming somatic cells into functional vascular cells with clear implications in cardiovascular regeneration and treatment.

6. Establishing novel cardiac and vascular organoids as well as heart/vessel-on-chip from human iPSCs for personalized cardiovascular medicine.
Traditional models including 2D cellular models and animal models have intrinsic and inherent limitations in fully capturing the intricacies of human tissue pathophysiology thereby reducing translational value and drug development potential. Recent advances has led to the development of cardiac and vascular organoids and heart/vessel-on-chip platforms. These novel stem cell based platforms can closely mimic the human cardiovascular system and pathophysiology, giving rise to high fidelity models that are superior to conventional models. Accordingly, my group seeks to develop novel cardiac and vascular organoids alongside heart/vessel-on-chip platforms from human iPSCs. Together with patient-specific iPSCs and gene editing tools, we hope to uncover disease aetiologies, investigate therapeutic interventions and conduct drug screening in a physiologically relevant context for the eventual goal of offering a personalized treatment for CVD (Figure 3).