Lungs serve as a major barrier to inhaled toxicants and have an inherent ability to regenerate following injury. However, prolonged or repeated damage can result in fibrosis and scar formation at the expense of regeneration, reducing the lungs’ ability to exchange oxygen. Now, research from the labs of Drs. Bi-Sen Ding, Ph.D., and Shahin Rafii, M.D., at Weill Cornell Medicine, define a novel role for capillary endothelial cells in modulating the process of regeneration and scar formation. Endothelial cells form the lining of blood vessels. Over a number of years, Dr. Rafii’s research has found that each tissue or organ has its own subset of endothelial cells, and these specialized endothelial cells regulate the functions of tissue-specific stem cells to control organ repair. Drs. Rafii and Ding discuss the instructive role of organ-specific endothelial cells in tissue repair and homeostasis in a recent review in Nature. They and others have already shown that tissue-specific endothelial cells do not just form passive conduits to deliver oxygen or nutrients, but by producing defined growth factors, known as angiocrine factors, induce organ regeneration without provoking scarring. As a proof of this principal the authors show that in the lungs, in response to damage, the endothelial cells produce signaling molecules that lead to expansion of alveolar epithelial cells, which replace the damaged tissue. However, repeated damage from exposure to toxicants can override this repair. Drs. Ding and Rafii now report in Nature Medicine on the signaling molecules behind these two opposing responses. Their findings identify a key role for the Wnt signaling pathway, and show that the Notch ligand Jagged1 is a key angiocrine molecule in stimulating scar formation in the damaged lungs. Inhibiting the activity of Jagged1 or activating a specific receptor, CXCR7, on endothelial cells, leads to repair and suppresses scar formation. Such approaches could potentially exploit the inherent pro-regenerative capacity of the organotypic vascular niche to develop therapies to repair lung damage. These papers were supported by NYSTEM contracts C024180, C026438, C026878, C028117 and C029156.
Cao Z, Lis R, Ginsberg M, Chavez D, Shido K, Rabbany SY, Fong GH, Sakmar TP, Rafii S, Ding BS. Targeting of the Pulmonary Capillary Vascular Niche Promotes Lung Alveolar Repair and Ameliorates Fibrosis. Nature Medicine. 2016 Jan 18 (Epub).
Rafii S, Butler JM, Ding BS. Angiocrine Functions of Organ-Specific Endothelial Cells. Nature. 2016 Jan 29, 529(7586).