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Tissue Repair & Regeneration


Identifying Therapeutic Approaches to Ectopic Calcification

Calcium in the body is mainly restricted to the skeletal system while soft tissues are devoid of calcium and remain elastic and pliable. Ectopic calcification refers to the abnormal calcification of extra-skeletal soft tissues. Many chronic diseases such as diabetes or chronic kidney disease cause ectopic calcification of the blood vessels and soft tissues. Abnormal calcification causes disruption of organ architecture and often leads to declining organ function. Clinical studies have demonstrated that ectopic calcification in conditions such as chronic kidney disease lead to many fold increase in mortality. Congenital bicuspid aortic valve disease, the most common congenital anomaly, that affects 1-2% of the population worldwide is characterized by progressive calcification of heart valves that require surgical correction. Despite the critical importance of pathologic ectopic calcification, no therapies exist for reversing or attenuating the progression of disease.


The Deb lab has demonstrated that ectopic calcification occurs secondary to abnormal plasticity of stromal cells that acquire an osteogenic phenotype and induce calcification of the extracellular matrix. We have identified that a critical protein ENPP1 plays a role in regulating calcification and are interested in understanding the role of ENPP1 in ectopic calcification and whether it can be therapeutically targeted for decreasing ectopic calcification. We also study rare genetic diseases such as Pseudoxanthoma Elasticum caused by mutations of the gene ABCC6, that result in abnormal mineralization of the internal structures of the eye and cause blindness. a laboratory, we use mouse models, human pluripotent stem cell modeling and other bioengineering and molecular approaches to understand the biology of ectopic calcification and identify therapeutic strategies for attenuating the progression of this incurable phenomenon.

ectopic calcification


(I) Confocal Raman microscopy demonstrating spectra of myocardial calcific deposits (blue line) compared to that of pure CPPD (black line) and hydroxyapatite (HA, red line) crystals (n = 3).  (J) Phosphate concentrations in injured and uninjured regions of non-calcified (B6) and calcified (C3H) hearts (mean ± SEM; n = 6 animals; ∗p < 0.01).  (K–P) Cryo-injured C3H animals treated with vehicle (K and M) or ENPP1 inhibitor, SYL-001 (L and N), or ARL67156 (O and P), demonstrating calcium deposition on gross inspection (K–O) and CT scan (M–P) and following 3D reconstruction (ribs removed to visualize cardiac calcification in retrosternal region) (yellow and white arrow).  (Q) Biochemical measurements of myocardial calcium deposits (n = 6 vehicle-treated, n = 9 SYL-001, and n = 5 ARL67156 animals, mean ± SEM, ∗p < 0.05 versus vehicle-injected group).  (R–U) Cryo-injured C3H animals treated with normal saline (R and S) or etidronate (T and U) demonstrating calcification on gross inspection (R and T) and CT scan (S and U) and following 3D reconstruction (yellow and white arrow). Note complete absence of any calcium deposits in the etidronate-injected animals (representative images of n = 3 for vehicle-treated animals and n = 6 for etidronate-injected animals).

Pillai ICL, Li S, Romay M, et al. Cardiac Fibroblasts Adopt Osteogenic Fates and Can Be Targeted to Attenuate Pathological Heart Calcification. Cell Stem Cell. 2017;20(2):218-232.e5. doi:10.1016/j.stem.2016.10.005

Scar Biology and Extracellular Matrix

Tissues that don't regenerate heal via a fibrotic repair response forming scar tissue. Even in tissues that regenerate, if the degree of injury and tissue damage overwhelms the regenerative response, wound healing takes place by scarring. Scar tissue is no longer thought to be dead tissue but considered to be a dynamic niche within the injured organ. Scar tissue comprises extracellular matrix proteins, fibroblasts, endothelial cells and other inflammatory cells that contribute towards tissue repair. The degree of scar tissue that forms after tissue injury such as after heart attacks has been shown to be an independent predictor of cardiac outcomes. Individuals with the same heart function but greater degree of scaring exhibit higher mortality rates and worse cardiac outcomes. However, little is known about how scar tissue size is regulated and the role of various matrix proteins in regulating scar size. The Deb lab has recently identified that type V collagen a minor constituent of scar tissue regulates the size of heart scars by modulating the mechanical properties of the matrix. Feedback between the mechanical properties of the scar and scar forming cells (fibroblasts) regulate how much more scar tissue proteins are secreted. The Deb lab uses genetic and physiological systems to interrogate the role of type V collagen and other proteins in regulating scar size as well as in genetic disorders that cause excessive scarring after minor injury.



Electron microscopy images showing a healthy scar containing collagen type 5 with scar fibers smoothly arranged in parallel (left) and unhealthy scar containing no collagen type 5 with a disorganized architecture with disarray of scar fibers (right).

Yokota T, McCourt J, Ma F, et al. Type V Collagen in Scar Tissue Regulates the Size of Scar after Heart Injury. 

Cell. 2020;182(3):545-562.e23. doi:10.1016/j.cell.2020.06.030

Plasticity and Crosstalk Between Cells Regulating Tissue Repair

The spatio-temporal events regulating wound healing are largely conserved across organs. Following acute injury, there is hemostasis (e.g. following skin injury), followed by recruitment of inflammatory cells, a proliferative phase characterized by proliferation of fibroblasts and endothelial cells and then a remodeling or maturation phase characterized by remodeling of the scar and associated structures. These phases of wound healing have parallel in most organs after tissue injury. The Deb lab investigates the various phases of wound healing in the heart, skin and multiple organs and identifies common targets that could regulate wound healing in multiple tissues. The Deb lab also studies cross talk between the various cells that are recruited to the region of injury and how cells get reprogrammed and acquire plasticity. We are currently studying the interface of cellular plasticity and metabolism and how metabolic cues are shared between cells to regulate tissue repair.



Cardiac fibroblasts upregulate p53 after injury and p53 mediates MEndoT ex vivo 

(a,b) p53 immunostaining in injured hearts (arrowheads show tdTomato+P53+ cells) (c) Temporal p53 expression in labeled fibroblasts (*p<0.05 vs sham, n=3 animals/time point).  (d) co-expression of p53, VECAD & tdTomato (arrowhead).  (e,f) tdTomato+VECAD+ tubes and (g,h) AcLDL uptake after serum starvation (arrowheads, n=4). Scale bar: 250μm (h, right panel) Confocal image (XZ plane) showing AcLDL internalization (Scale bar: 20μm).  (i–m) Tube formation of cardiac fibroblasts in (i)10% serum or 0% serum with (j) PBS (k) 100μM Pifithrin-α, (m) 0.1μM RITA, or (l) p53 deletion (bright field and fluorescence overlay). Scale bar: 250μm (n) Quantitation of tube length (** p<0.005 vs 10% serum. † p<0.005 and *p<0.05 vs starved cells, n=3).  (o) Endothelial gene expression in cardiac fibroblasts (* p<0.005 vs 10% serum, † p<0.05 vs PBS, n=8).  (p) ChIP with p53 (*p<0.05). (All graphs show mean±S.E.M., scale bar: 10μm unless mentioned).

Ubil, E., Duan, J., Pillai, I. et al. Mesenchymal–endothelial transition contributes to cardiac neovascularization. Nature 514, 585–590 (2014).

Disease modeling in a dish using human pluripotent stem cells for treating rare genetic diseases

We use hiPSC technology in association with precise genome editing with Crispr/Cas to induce genetic mutations that are causally related with many rare diseases. Following the introduction of mutations, we differentiate the hPSC into cardiac muscle cells or other cells of choice to determine if the human phenotype is recapitulated in the dish. Such human “disease in a dish approach” enables rapid identification of (i) cellular signaling pathway abnormalities (ii) screening of libraries or biologics to identify potential druggable compounds and finally, we create mouse models to validate the lessons we have learned from ‘disease in a dish” modeling. Such approaches, we hope will accelerate the therapy of rare genetic diseases.

Human pluripotent stem cell-derived cardiomyocytes.

Supporting our avenues of investigation, we have a robust medicinal chemistry and biologics program that we use as tools to identify novel therapies for molecular targets we have identified in any of the above areas of investigation. These efforts have led us to co-found start up companies to accelerate the translation of these technologies to the clinic.

Funding Support
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