Lung Progenitor Cell Transplantation for Pulmonary Fibrosis and Ex Vivo Expansion of Patch-Forming EpCAM⁺CD31⁺ Cells

<p>Idiopathic pulmonary fibrosis (IPF) and other chronic interstitial lung diseases are characterized by progressive destruction of the alveolar architecture, leading to irreversible respiratory failure. Although recent pharmacologic interventions can slow disease progression, lung transplantation remains the only curative option—yet its use is limited by donor scarcity and poor post-transplant survival related to the procedure. Previous studies in our group demonstrated the lung regenerative potential of simple lung cell transplantation in the well-established mouse model of naphthalene induced pulmonary injury, by either the entire lung cell population or only by the CD45- subpopulation. More recent FACS sorting experiments revealed that this curative potential resides within the small CD45-CD326+CD31+ subpopulation. However, these studies also indicated that in this mouse model successful transplantation requires vacating the lung niches in recipient mice of endogenous lung progenitors which otherwise compete with donor derived progenitors for their respective lung niches. Based on these findings, this thesis investigates the therapeutic potential of lung cell transplantation in two distinct mouse models of pulmonary fibrosis, demonstrating that endogenous lung progenitors are lost upon progression of fibrosis and thereby the stem cell competition is diminished, allowing successful transplantation without any need for pre-conditioning of the recipients with toxic agents. Thus, intravenous infusion of freshly isolated lung cells resulted in robust donor-derived chimerism within the injured host lungs. Transplanted cells formed discrete patches composed of alveolar type I (AQP5⁺, RAGE⁺) and type II (SPC⁺, LAMP3⁺) epithelial cells, endothelial (CD31⁺, ERG⁺), and mesenchymal (PDGFRα⁺) cells. Engraftment was associated with marked histologic and radiographic improvement, reduced collagen deposition, and restored pulmonary function, demonstrating true tissue regeneration.</p> <p>To overcome the inherently low yield of primary CD326+CD31+ lung progenitors from cadaveric lungs which can generally suffice for transplantation in 1-2 patients, we interrogated the possibility of expanding these progenitor cells ex-vivo. Thus, a culture system was established to promote expansion while preserving progenitor identity and regenerative potential. Through targeted modulation of cell-signaling pathways and optimization of the growth environment, a significant amplification of EpCAM⁺CD31⁺ progenitors without loss of phenotypic stability or engraftment capacity has been established.</p> <p>These findings lay the foundation for developing safe and reproducible cellular therapies for patients with pulmonary fibrosis.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2025

Authors dc:creator

• Zheng, Yangxi
• <p>0000-0002-7423-0090</p>

Contributors dc:contributor

• Yair Reisner, Ph.D.
• Burton F. Dickey, M.D.
• Jeffrey J. Molldrem, M.D.

• stem cell transplantation
• pulmonary fibrosis
• stem cell
• cellular therapy
• Biology
• Cell and Developmental Biology
• Immunology and Infectious Disease
• Life Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1499

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2556