The only available treatment for end stage lung diseases is a total 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 in many mammalian species. 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. 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. Recently macrophages have been implicated in tissue repair and regeneration, but little is know about their role in lung regeneration. We are using 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 will assess how macrophages may contribute to the regenerative niche of distal lung epithelial stem cells to promote adult alveologenesis post-PNX. We propose to first measure immune cell population dynamics and activation states post-PNX (Aim 1). Our preliminary data shows that that CD115+ myeloid cells increase in regenerating lung post-PNX and a subset of these cells co-express Arginase-1, a marker of M2-polarized macrophages shown previously to promote wound healing. We will further characterize the myeloid population dynamics post-PNX and determine if these cells increase by local proliferation or are derived from circulating monocytes. We will then test the requirement for macrophages in PNX-induced lung regeneration (Aim 2). Interestingly, the chemokine CCL2 is upregulated in lung epithelium post-PNX. We will disrupt CCL2 in the epithelium or its cognate receptor, CCR2, and determine how this impairs lung regeneration. Finally, our preliminary data suggests post-PNX macrophages secrete factors that could promote angiogenesis. We will investigate whether macrophages directly influence AEC2 proliferation post-PNX or if they indirectly influence AEC2 by promoting angiogenesis, which is required for PNX-induced lung regeneration (Aim 3). We will determine if endothelial proliferation is impaired in CCR2 knock-out mice and identify macrophage-specific pro-angiogenic pathways. We hope to identify mechanisms 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.
One treatment option for patients with end-stage lung disease is to harness the potential of endogenous adult lung stem cells to regenerate new lung tissue. Unfortunately, many questions remain regarding the identity of human lung epithelial stem cells and the external and internal mechanisms regulating their activation. The proposed studies on the lung epithelial stem cell microenvironment have the potential to lead to the development of novel clinical therapies for patients with lung disease.
| Lechner, Andrew J; Driver, Ian H; Lee, Jinwoo et al. (2017) Recruited Monocytes and Type 2 Immunity Promote Lung Regeneration following Pneumonectomy. Cell Stem Cell 21:120-134.e7 |
| Kanegai, Cindy M; Xi, Ying; Donne, Matthew L et al. (2016) Persistent Pathology in Influenza-Infected Mouse Lungs. Am J Respir Cell Mol Biol 55:613-615 |
