Identification of dedifferentiation and redevelopment phases during postpneumonectomy lung growth

Abstract

Surgical resection of pulmonary tissue exerts a proregenerative stretch stimulus in the remaining lung units. Whether this regeneration process reenacts part or whole of lung morphogenesis developmental program remains unclear. To address this question, we analyzed the stretch-induced regenerating lung transcriptome in mice after left pneumonectomy (PNX) in its developmental context. We created a C57BL/6 mice lung regeneration transcriptome time course at 3, 7, 14, 28, and 56 days post-PNX, profiling the cardiac and medial lobes and whole right lung. Prominent expression at days 3 and 7 of genes related to cell proliferation (Ccnb1, Bub1, and Cdk1), extracellular matrix (Col1a1, Eln, and Tnc), and proteases (Serpinb2 and Mmp9) indicated regenerative processes that tapered off after 56 days. We projected the post-PNX transcriptomic time course into the transcriptomic principal component space of the C57BL/6 mouse developing lungs time series from embryonic day 9.5 to postnatal day 56. All post-PNX samples were localized around the late postnatal stage of developing lungs. Shortly after PNX, the temporal trajectory of regenerating lobes and right lung reversed course relative to the developing lungs in a process reminiscent of dedifferentiation. This reversal was limited to the later postnatal stage of lung development. The post-PNX temporal trajectory then moves forward in lung development time close to its pre-PNX state after days 28 to 56 in a process resembling redevelopment. A plausible interpretation is that remaining pulmonary tissue reverts to a more primitive stage of development with higher potential for growth to generate tissue in proportion to the loss.