Regeneration of functional alveoli by adult human SOX9+ airway basal cell transplantation

Abstract

Irreversible destruction of bronchi and alveoli can lead to multiple incurable lung diseases. Identifying lung stem/progenitor cells with regenerative capacity and utilizing them to reconstruct functional tissue is one of the biggest hopes to reverse the damage and cure such diseases. Here we showed that a rare population of SOX9+ basal cells (BCs) located at airway epithelium rugae can regenerate adult human lung. Human SOX9+ BCs can be readily isolated by bronchoscopic brushing and indefinitely expanded in feeder-free condition. Expanded human SOX9+ BCs can give rise to alveolar and bronchiolar epithelium after being transplanted into injured mouse lung, with air-blood exchange system reconstructed and recipient’s lung function improved. Manipulation of lung microenvironment with Pirfenidone to suppress TGF-β signaling could further boost the transplantation efficiency. Moreover, we conducted the first autologous SOX9+ BCs transplantation clinical trial in two bronchiectasis patients. Lung tissue repair and pulmonary function enhancement was observed in patients 3–12 months after cell transplantation. Altogether our current work indicated that functional adult human lung structure can be reconstituted by orthotopic transplantation of tissue-specific stem/progenitor cells, which could be translated into a mature regenerative therapeutic strategy in near future.Electronic supplementary materialThe online version of this article (10.1007/s13238-018-0506-y) contains supplementary material, which is available to authorized users.

Clonal expansion of hepatic progenitor cells and differentiation into hepatocyte‐like cells

“…Hepatic progenitor cells were isolated based on published methods for lung stem cells (Ma et al., ; Zuo et al., ) with minor changes. Briefly, mT/mG mice at the age of 6–8 weeks were anesthetized by intraperitoneal injection with ketamine hydrochloride (20 mg/kg) and xylazine (5 mg/kg), and the liver tissue was perfused with 50 ml D‐Hanks Solution.…”

“…Hepatic progenitor cells were isolated based on published methods for lung stem cells (Ma et al, 2018;Zuo et al, 2015) with minor changes.…”

Isolation and long-term expansion of a single adult human renal epithelial cell with efficient kidney regeneration capacity

“…In order to investigate the organ-specificity of SOX9+ REC mediated regeneration, we compared the kidney-derived SOX9+ REC with human lung-derived SOX9+ basal cells 42 .…”

Demise of lung transplants: exposing critical gaps in understanding lung stem cells

“…Importantly, these same p63+/Krt5+ DASCs showed no incorporation in mice absent acute lung injury, suggesting that the efficient regenerative properties of these cells are not marred by "off-target" incorporation (10). Lastly, DASC's are readily cloneable from simple bronchoscopic biopsies, from bronchopulmonary lavage, or from transmural biopsies, providing good sources of autonomous stem cells that can be expanded to hundreds of billions of cells in four weeks (10)(11)(12)(13)(14)(15)(16)(17). Taken together, the established properties of DASCs, including clonogenicity, expandability, and facility for accurate transplantation obviate many theoretical objections that could have limited their use in regenerative medicine.…”

“…However, the most significant problem presented by chronic lung conditions is the vast remodeling of these lungs that, despite the pathology, is devoid of active necrotizing domains known to be critical for the regenerative process in lung and almost all other organs known to undergo a regenerative response. Simply delivering populations of autologous stem cells to such patients is unlikely to favorably impact outcome and could negatively impact enthusiasm for cell-based therapeutics in general (17). Thus, the key challenge for resolving chronic lung conditions will be to devise highly controlled and sterile means of inducing a necrotizing damage of discrete regions of the lung.…”