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p63+Krt5+ distal airway stem cells are essential for lung regeneration
Wei Zuo,
Ting Zhang,
Daniel Zheng'An Wu,
Shou Ping Guan,
Audrey-Ann Liew,
Yusuke Yamamoto,
Xia Wang,
Siew Joo Lim,
Matthew Vincent,
Mark Lessard,
Christopher P. Crum,
Wa Xian
& Frank McKeon
Nature
(2014)
doi:10.1038/nature13903
Received
30 March 2014
Accepted
30 September 2014
Published online
12 November 2014
Lung diseases such as chronic obstructive pulmonary disease1 and pulmonary fibrosis2 involve the progressive and inexorable destruction of oxygen exchange surfaces and airways, and have emerged as a leading cause of death worldwide. Mitigating therapies, aside from impractical organ transplantation, remain limited and the possibility of regenerative medicine has lacked empirical support. However, it is clinically known that patients who survive sudden, massive loss of lung tissue from necrotizing pneumonia3, 4 or acute respiratory distress syndrome5, 6 often recover full pulmonary function within six months. Correspondingly, we recently demonstrated lung regeneration in mice following H1N1 influenza virus infection, and linked distal airway stem cells expressing Trp63 (p63) and keratin 5, called DASCp63/Krt5, to this process7. Here we show that pre-existing, intrinsically committed DASCp63/Krt5 undergo a proliferative expansion in response to influenza-induced lung damage, and assemble into nascent alveoli at sites of interstitial lung inflammation. We also show that the selective ablation of DASCp63/Krt5 in vivo prevents this regeneration, leading to pre-fibrotic lesions and deficient oxygen exchange. Finally, we demonstrate that single DASCp63/Krt5-derived pedigrees differentiate to type I and type II pneumocytes as well as bronchiolar secretory cells following transplantation to infected lung and also minimize the structural consequences of endogenous stem cell loss on this process. The ability to propagate these cells in culture while maintaining their intrinsic lineage commitment suggests their potential in stem cell-based therapies for acute and chronic lung diseases.
Share/bookmark
p63+Krt5+ distal airway stem cells are essential for lung regeneration
Wei Zuo,
Ting Zhang,
Daniel Zheng'An Wu,
Shou Ping Guan,
Audrey-Ann Liew,
Yusuke Yamamoto,
Xia Wang,
Siew Joo Lim,
Matthew Vincent,
Mark Lessard,
Christopher P. Crum,
Wa Xian
& Frank McKeon
Nature
(2014)
doi:10.1038/nature13903
Received
30 March 2014
Accepted
30 September 2014
Published online
12 November 2014
Lung diseases such as chronic obstructive pulmonary disease1 and pulmonary fibrosis2 involve the progressive and inexorable destruction of oxygen exchange surfaces and airways, and have emerged as a leading cause of death worldwide. Mitigating therapies, aside from impractical organ transplantation, remain limited and the possibility of regenerative medicine has lacked empirical support. However, it is clinically known that patients who survive sudden, massive loss of lung tissue from necrotizing pneumonia3, 4 or acute respiratory distress syndrome5, 6 often recover full pulmonary function within six months. Correspondingly, we recently demonstrated lung regeneration in mice following H1N1 influenza virus infection, and linked distal airway stem cells expressing Trp63 (p63) and keratin 5, called DASCp63/Krt5, to this process7. Here we show that pre-existing, intrinsically committed DASCp63/Krt5 undergo a proliferative expansion in response to influenza-induced lung damage, and assemble into nascent alveoli at sites of interstitial lung inflammation. We also show that the selective ablation of DASCp63/Krt5 in vivo prevents this regeneration, leading to pre-fibrotic lesions and deficient oxygen exchange. Finally, we demonstrate that single DASCp63/Krt5-derived pedigrees differentiate to type I and type II pneumocytes as well as bronchiolar secretory cells following transplantation to infected lung and also minimize the structural consequences of endogenous stem cell loss on this process. The ability to propagate these cells in culture while maintaining their intrinsic lineage commitment suggests their potential in stem cell-based therapies for acute and chronic lung diseases.
