Mentor: Stephen McGowan, M.D.
Lab Phone: 158-7606

Investigating PDGFA/PDGFRa signaling in alveolar fibroblast to myofibroblast transdifferentiation

The myofibroblast is a specialized fibroblast that is present during wound healing, is critical for the development of fibrotic states such as hepatic cirrhosis and pulmonary interstitial fibrosis, and is also required for normal development of the pulmonary alveoli. Myofibroblasts are morphologically and functionally intermediate between fibroblasts and smooth muscle cells. Myofibroblasts differ from other smooth muscle cells (a) in their architecture, (b) they are not located around blood vessels or bronchial walls and (c) they express α-smooth muscle actin (α-SMA) and desmin but lack myosin. Like smooth muscle cells, myofibroblasts produce elastin, a major component of the elastic fiber, which is required to maintain the normal mechanical properties of the lung.

Developmental mouse studies have demonstrated that platelet-derived growth factor A (PDGF-A) and its cognate receptor, PDGFR-α, are required to initiate and maintain myofibroblasts in developing alveoli. However, the mechanisms involved in the process remain unclear. Our studies involve determining how PDGF-A/PDGFR-α signaling may stimulate the myofibroblast phenotype (α-SMA production) and function (elastin expression). Our experimental model is a transgenic mouse that expresses green fluorescent protein under the control of the endogenous PDGFR-α promoter, allowing us to be able to distinguish PDGFR-α expressing cells in the lung, and characterize the fibroblastic phenotype and function of these cells.

Publications

Kimani PW, Holmes AJ, Grossmann RE, McGowan SE. PDGF-Ralpha gene expression predicts proliferation, but PDGF-A suppresses transdifferentiation of neonatal mouse lung myofibroblasts. Respir Res. 2009 Nov 25;10:119. PubMed PMID: 19939260; PubMed Central PMCID: PMC2799395.

McGowan SE, Grossmann RE, Kimani PW, Holmes AJ. Platelet-derived growth factor receptor-alpha-expressing cells localize to the alveolar entry ring and have characteristics of myofibroblasts during pulmonary alveolar septal formation. Anat Rec (Hoboken). 2008 Dec;291(12):1649-61. PubMed PMID: 18833569.

Abstracts:

Kimani, P.K., and McGowan, S.E. The role of Platelet-derived Growth Factor A in Pulmonary Myofibroblast Differentiation and Function during Alveolar Development. American Thoracic Society Annual Meeting, San Fransisco, CA, 2007.

Kimani, P.K., and Phelps, C.J. Dopaminergic neurons that also produce GHRH: Quantification of a subpopulation in the mouse arcuate nucleus using double immunofluorescence. Society for Neuroscience Annual Meeting, New Orleans, LA, 2003.