Research Overview

Our lab studies the regulatory mechanisms of adult stem cells in various tissues, and the interaction between stem cells and their niche. We focus our efforts on Procr (protein C receptor), which has been established as a surface marker of adult stem cells in multiple tissues.

Our long-term goal is to determine how the stem cell regulatory mechanisms have deviated in diseases and cancer, and to learn how to control the players in these machineries in vivo, as well as to provide ever-expanding stem cells in vitro for the purpose of regenerative medicine.

Procr Stem Cells

Procr is a single pass transmembrane receptor. Our work identifies Procr as a Wnt signaling target, and Procr-expressing cells are stem cells in the mammary gland (Nature 2015). Subsequently, we show that Procr marks the stem cells in vascular endothelium (Cell Research 2016), ovarian surface epithelium (Nature Communications 2019) and pancreatic islets (Cell 2020). Works from Richard Mulligan, Toshio Suda, Bing Liu, and Guy Sauvageau labs also indicate that Procr (also named EPCR, CD201) marks the stem cell in hematopoietic system in both mouse and human. These combined insights suggest that Procr is a general stem cell maker for multiple tissues. Through collaborations, we are on the path to uncover more tissues in which the stem cells are marked by Procr, and to understand the functional role of Procr and its molecular mechanisms of action in stem cells.

Procr in Cancer and Disease

Procr expression is prevalent in human triple-negative breast cancers, and Procr+ cells in cancer are still coupled with stem cell characteristics, exhibiting robust tumorigenic capability. We developed inhibitory nanobody (single chain monoclonal antibody) for the treatment of this particular type of breast cancer (Cell Research 2019). We also uncovered Procr intracellular signaling in breast cancer cells (JBC 2018). Through collaborations with clinicians, we are profiling Procr expression in cancers of various organs. We hope to extend the use of Procr in cancer diagnosis and therapy. On the flip side, for degenerative disease such as diabetes that associated with beta cell loss, we aim to exponentially expand Procr pancreatic islet stem cells and their progeny beta cells in vitro for long-term (Cell 2020). The goal is to provide unlimited beta cells for the cell therapy of diabetes.

Hormones, The Niche and The Immune Environment

The development of many organs is governed by the concerted action of systemic hormones and local growth factors. For example, we found that in the mammary gland, the expression of local niche factors, Wnt4 and Rspo1 are regulated by ovarian hormones (Genes and Dev 2014). We aim to have a better understanding of the molecular mechanisms through which hormones regulate the activity of tissue resident stem cells.

In addition, current niche theory portraits the stem cell being permissive to receive signals from the niche, hence making decision for self-renewal or differentiation. We hypothesize that the stem cell can play an instructive role when interact with its niche. We aim to understand how the stem cell orchestrates its niche signals. One approach is to identify novel signals emanating from Procr stem cells and study their crosstalk with the known niche components including fibroblasts, immune cells and endothelial cells in development and in regeneration.