Submitted on July 30, 2007
Accepted on March 20, 2008
Cellular kinetics and modeling of bronchioalveolar stem cell response during lung regeneration
ROSE DUNBAR NOLEN-WALSTON1, Carla F. Kim2, Melissa R. Mazan3, Edward P Ingenito4, Alisha M Gruntman3, Larry Tsai4, Ray C. Boston5, Amber E Woolfenden6, Tyler Jacks6, and Andrew M. Hoffman7*
1 CLINICAL SCIENCES, UNIVERSITY OF PENNSYLVANIA, KENNETT SQUARE, Pennsylvania, United States
2 Stem Cell Program, Children's Hospital , 300 Longwood Ave., Boston, Massachusetts, 02115, United States; Department of Biology and Center for Cancer Research, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Boston, Massachusetts, United States
3 Clinical Sciences, Tufts University School of Veterinary Medicine, North Grafton, Massachusetts, United States
4 Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States
5 Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Pennsylvania, Pennsylvania, United States
6 Department of Biology and Center for Cancer Research, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Boston, Massachusetts, United States
7 Clinical Sciences, Tufts University, North Grafton, Massachusetts, United States
* To whom correspondence should be addressed. E-mail: andrew.hoffman{at}tufts.edu.
Organ regeneration in mammals is hypothesized to require a functional pool of stem or progenitor cells, but the role of these cells in lung regeneration is unknown. Whereas postnatal regeneration of alveolar tissue has been attributed to type II alveolar epithelial cells (AECII), we reasoned that bronchioalveolar stem cells (BASCs) have the potential to contribute substantially to this process. To test this hypothesis, unilateral pneumonectomy (PNX) was performed on adult female C57/BL6 mice to stimulate compensatory lung regrowth. The density of BASCs and AECII, and morphometric and physiologic measurements were recorded on days 1, 3, 7, 14, 28, and 45 days after surgery. Vital capacity was restored by day 7 after PNX. BASC numbers increased by day 3, peaked to 220% of controls by day 14, then returned to baseline after active lung regrowth was complete, whereas AECII cell densities did not significantly change. Proliferation studies revealed significant BrdU uptake in BASCs and AECII within the first 7 days after PNX. Quantitative analysis using a systems biology model was used to evaluate the potential contribution of BASCs and AECII. The model demonstrated that BASC proliferation and differentiation contributes between 0 and 25% of compensatory lung regrowth, demonstrating that regrowth requires a substantial contribution from AECII. The observed cell kinetic profiles can be reconciled using a dual-compartment (BASC and AECII) proliferation model assuming a linear hierarchy of BASCs, AECII and AECI cells to achieve lung regrowth.
