Congratulations to Andrew Lechner, who's giving his thesis seminar titled, “Recruited monocytes and M2-like macrophages promote lung regeneration.” If you can, please come out to support Andrew as he finishes up his graduate work!
When: Monday, March 13, 10:00am
Where: N-225, Parnassus
Host: Jason Rock, PhD
The only current treatment for end stage lung diseases is a full lung transplant. This procedure is limited by poor survival and an inadequate supply of donor lungs. An alternative is to promote regeneration of normal lung tissue from endogenous progenitor cells. Partial pneumonectomy (PNX), the surgical removal of one or more lobes, stimulates compensatory lung growth in the remaining lobes. This model of adult alveologenesis is mediated by proliferation of several progenitor populations, including alveolar epithelial type 2 cells (AEC2s), which are distal lung epithelial stem cells. Recently macrophages have been implicated in tissue repair and regeneration, but little is known about how these or other immune cells participate in lung regeneration.
We have found that CD115+ monocytes and macrophages accumulate in the remaining uninjured lung lobes during the peak of AEC2 proliferation post-PNX. Single cell RNA sequencing identified myeloid subpopulations in regenerating lungs, including CCR2+ monocytes and M2-like macrophages. Genetic loss of function in mice and adoptive transfer studies revealed that bone marrow-derived macrophages are recruited to the lung through a CCL2-CCR2 chemokine axis and are required for optimal lung regeneration. Lung macrophages promote regeneration through matrix remodeling in vivo and we provide in vitro evidence that they directly support AEC2 survival and proliferation.
Bone marrow chimerism demonstrated that IL-4Rα-mediated Th2 signaling is required on leukocytes for polarization of Arginase1+ M2-like macrophages that are also required for lung regeneration. Our data suggest that both CCR2+ monocytes and Arginase1+ M2-like macrophages modulate AEC2 proliferation and differentiation in vivo. Finally, we provide evidence that ILC2s accumulate in the lungs post-PNX and are a source of IL13 that polarizes M2-like macrophages. Together, our data highlight the potential for immunomodulatory therapies to stimulate alveologenesis in adults.