Altered expression of p63 isoforms and expansion of p63- and club cell secretory protein-positive epithelial cells in the lung as novel features of aging

Author:

Fukumoto Jutaro1,Sidramagowda Patil Sahebgowda1,Krishnamurthy Sudarshan1,Saji Smita1,John Irene1,Narala Venkata Ramireddy12,Hernández-Cuervo Helena13,Alleyn Matthew1,Breitzig Mason T.1,Galam Lakshmi1,Soundararajan Ramani1,Chaudhari Uddhav K.4,Hansen Barbara C.4,Lockey Richard F.1,Kolliputi Narasaiah13

Affiliation:

1. Division of Allergy and Immunology, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida

2. Department of Zoology, Yogi Vemana University, Kadapa, India

3. Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida

4. Departments of Internal Medicine and Pediatrics, Morsani College of Medicine, University of South Florida, Tampa, Florida

Abstract

Aging is a key contributor for subclinical progression of late-onset lung diseases. Basal, club, and type II alveolar epithelial cells (AECs) are lung epithelial progenitors whose capacities of differentiation are extensively studied. The timely transition of these cells in response to environmental changes helps maintain the intricate organization of lung structure. However, it remains unclear how aging affects their behavior. This paper demonstrates that the protein expression profiles of a type II AEC marker, prosurfactant protein C (pro-SPC), and a basal cell marker, p63, are altered in the lungs of 14-mo-old versus 7- to 9-wk-old mice. Expression of NH2-terminal-truncated forms of p63 (ΔNp63), a basal cell marker, and claudin-10, a club cell marker, in cytoplasmic extracts of lungs of 14-mo-old mice was upregulated. In contrast, nuclear expression of full-length forms of p63 (TAp63) decreases with age. These alterations in protein expression profiles coincide with dramatic changes in lung functions including compliance. Whole tissue lysates of middle-aged versus aged rhesus monkey lungs display similar age-associated alterations in pro-SPC expression. An age-associated decrease of TAp63 in nuclear lysates was observed in aged monkey group. Moreover, the lungs of 14-mo-old versus 7- to 9-wk-old mice display a wider spreading of ΔNp63-positive CCSP-positive bronchiolar epithelial cells. This expansion did not involve upregulation of Ki67, a representative proliferation marker. Collectively, it is postulated that 1) this expansion is secondary to a transition of progenitor cells committed to club cells from ΔNp63-negative to ΔNp63-positive status, and 2) high levels of cytoplasmic ΔNp63 expression trigger club cell migration.

Funder

American Heart Association (AHA)

National Institutes of Health (NIH)

National Institute on Aging (U.S. National Institute on Aging)

Jon McCann Culverhouse Endowment to the Division of Allergy and Immunolgy

Publisher

American Physiological Society

Subject

Cell Biology,Physiology

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