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Recruited Monocytes and Type 2 Cytokines Promote Lung Regeneration

  • Author(s): Lechner, Andrew John
  • Advisor(s): Werb, Zena
  • et al.
Abstract

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 their role in lung regeneration. Significant questions remain regarding the regenerative potential of human lungs, the identities of human lung epithelial stem cells, the molecular signals that control their activation, and the influences of the microenvironment on regeneration. Our objective is to apply data from murine studies to stimulate regeneration of human lungs.

We use fluorescent reporters and genetic gain- and loss-of function in mice to identify populations of immune cells that modulate epithelial stem cell behaviors in adult lung regeneration. We hope to identify molecular targets that mediate these effects that might be exploited to stimulate lung regeneration and may be developed into novel therapies for patients with end-stage lung disease.

We have found that CD115+ monocytes and macrophages accumulate in the remaining uninjured lung lobes during the peak of proliferation of type 2 alveolar epithelial stem cells (AEC2s). 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. 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 these cells modulate AEC2 proliferation and differentiation. Finally, we provide evidence that ILC2s are a source of IL13 that polarizes M2-like macrophages. Together, our data highlight the potential for immunomodulatory therapies to stimulate alveologenesis in adults.

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