Tissues of multicellular organisms consist of various cell types that are derived from different developmental origins and these cells interact and affect functions of each other while being embedded in an extracellular matrix (ECM). Importantly, ECM not only supports these cells in tissue microenvironments, but also regulates their functions. It is now well-appreciated that ECM influences a wide number of cellular processes including migration, proliferation, differentiation, and wound healing through changes in stiffness, serving a reservoir of myriad of growth factors, and, most importantly, direct signaling to cells. Our research has been focused on the study of cellular communication network factor 1 (CCN1/CYR61), a matricellular protein and its driven cellular signaling and implication in injury repair and regeneration in various tissues. CCN1 is functionally a multifaceted protein, playing essential roles in regulating inflammation and wound healing and recently being recognized as an important factor in stem cell lineage specification and tissue regeneration. We have developed various mouse genetic models which include two allelic series of knock-in mice expressing an integrin binding defective CCN1 mutant. These knock-in mice have been instrumental in the dissection of integrin-dependent CCN1 functions in vivo. In addition, Ccn1flox/flox mice allow Cre-mediated cell type-specific deletion of Ccn1.

Ongoing research projects:

(1) Importance of the CCN1-matricellular signaling in regulating intestinal injury repair by controlling the dedifferentiation of epithelial cells to restore intestinal stem cell (ISC) pool. While minor superficial injury is repaired through the homeostatic proliferation and differentiation of ISCs, when damages would reach to ISCs, resulting in the loss of stem cell pool, regeneration can only occur upon restoration of stem cells through reprogramming of progenitor or even fully differentiated cells to dedifferentiate into ISCs. Our results from Ccn1D125A/D125A knockin mice and mice with Ccn1 deletion in Lgr5+ ISCs suggest that CCN1 might be critically involved in these processes upon such severe injuries, such as chemical (Dextran Sulfate Sodium-induced colitis) and radiation (X-ray irradiation) as well as targeted elimination of Lgr5+ ISCs (using Diphtheria toxin-mediated targeted ablation). Using single cell-RNA sequencing (scRNA-seq), lineage-tracing, and organoids experiments, we are investigating novel functions of CCN1-matricellular signaling in stem cell restoration for regeneration.

(2) Induction of fibroblast senescence in the stroma and its reparative function during epithelial regeneration. Cellular senescence is a permanent growth arrest state into which cells are driven under stress and damage conditions. It is also perceived as a cellular aging response, as senescent cells secrete various factors that may impose tissues with deleterious effects when they persist chronically. However, we discovered that an acute and transient senescence rather occurs as a wound-healing process and factors from senescent cells, senescence-associated secretory phenotypes (SASPs), are beneficial for fibrosis resolution and regeneration. We are investigating which factor or combination of factors, collectively called senescence regeneration factor (SRF), from senescent cells in the stroma could promote intestinal epithelial regeneration upon injuries.

(3) Regulation of host immune response during poly microbial sepsis. One of key recent findings is that CCN1 promotes phagocytosis and killing of bacteria by macrophages and neutrophils. As wounds are prone to infection during repair and although antibiotics showed efficacy to eliminate infected pathogens, they often acquire resistance to antibiotics, which poses great threat to global health, our finding provides a novel insight on new treatment options, by which activation of cellular defense mechanisms by CCN1-matricellular signaling may provide defense against antibiotic resistant bacterial infections. Moreover, another important discovery is that CCN1 directly interacts with Toll-like receptors (TLR2/4), independent of its phagocytic activity. Thus, based on these results, we hypothesize that host innate immune systems may be finely tuned by CCN1-matricellular signaling and we will scrutinize how phagocytosis and TLR signaling are coordinated by CCN1 at the molecular levels and how these functions influence host immune response using a mouse model of poly microbial sepsis.

(4) Regulation of microbiome landscape and gut health. Human gut harbors a complex community of over 1000 trillions of microorganisms which influences physiology, nutrition, and immune functions while disruption of gut microbiota has been linked to gastrointestinal (GI) conditions such as inflammatory bowel disease (IBD) and obesity. As described above, CCN1-matricellular signaling is implicated in host response against bacteria. Therefore, we anticipate that manipulation of ECMs or their signaling may change microbiome landscapes, potentially affecting homeostasis and pathologies. In our preliminary studies, 16S sequencing of the gut microbiome shows changes in Taxa abundance and/or ratio between Firmicutes and Bacteroidetes in Ccn1 mutant mouse strains, strengthening our idea that changes in ECM modifies microbiome landscape and thus showing the potential to the future research programs.