Mapping Cells to Provide Drug Targets For Lung Disorders
Recent studies have shown that the respiratory system has an extensive ability to respond to injury and regenerate lost or damaged cells. The unperturbed adult lung is remarkably quiescent, but after insult or injury progenitor populations can be activated or remaining cells can re-enter the cell cycle.
Techniques including cell-lineage tracing and transcriptome analysis have provided novel and exciting insights into how the lungs and trachea regenerate in response to injury and have allowed the identification of pathways important in lung development and regeneration.
Now, using single-cell RNA sequencing and signaling lineage scientists at the University of Pennsylvania have generated a spatial and transcriptional map of the lung mesenchyme that they believe could provide drug targets for disorders like pulmonary fibrosis.
“We need better targets,” said senior author Edward E. Morrisey, PhD, a professor of Cell and Developmental Biology, and director of the Penn Center for Pulmonary Biology. “All we have now are blunt sledge hammers that don’t work” for conditions such as idiopathic pulmonary fibrosis (IPF), a lung disorder whose cause is poorly understood.
“The lung is one of the most complex organs in the human body,” Morrisey said, “The complicated
structure of lungs is why it is difficult to quickly diagnose the exact type of lung disease a person may have with any certainty,” he said. “Also, as there is considerable reserve capacity in our lungs most people are not diagnosed with lung diseases such as IPF until the disease has progressed significantly.” This biological compensation mechanism means that a person could lose almost 50 percent of their lung function before feeling any symptoms.Knowing the specific cells and pathways that promote repair and regeneration versus scar formation in the lung will help inform the development of more precise and effective therapies.
In the course of the study, the team analyzed secreted molecules and surface cell receptors from the cells of interest, and compared this information to databases of known secreted molecules and receptors on adjacent cells.
One cell type the Morrisey lab identified in the mouse lung that governs self-renewal of cell populations is called the Mesenchymal Alveolar Niche Cell (MANC). These cells are critical for the regeneration of lung alveoli. The second cell type is called the Axin2+ Myofibrogenic Progenitor cell (AMP), which generates cells called myofibroblasts that form scar tissue after injury, and likely contribute to diseases such as IPF.
“The mesenchymal alveolar niche cell is WNT responsive, expresses Pdgfrα, and is critical for alveolar epithelial cell growth and self-renewal,” the article’s authors detailed. “In contrast, the Axin2+ myofibrogenic progenitor cell preferentially generates pathologically deleterious myofibroblasts after injury. Analysis of the secretome and receptome of the alveolar niche reveals functional pathways that mediate growth and self-renewal of alveolar type 2 progenitor cells, including IL-6/Stat3, Bmp, and Fgf signaling.”
The “good” MANCs are found in niches or compartments near the alveoli to promote renewal of gas-exchange cells. They may play a key role in maintaining the alveoli during the normal life span of the adult. Dysfunction or loss of MANCs may contribute to diseases such as COPD, which involves loss of alveoli and decreased lung function. The role of the “bad” AMPs is to form scar tissue during wound healing. However, AMPs may grow out of control, potentially leading to diseases such as IPF.
Further, the researchers aim to identify these cell types in humans. Dr. Morrisey indicated that the Penn team wants to target MANCs for promoting regeneration while inhibiting AMPs to reduce the fibrotic response after injury. Knowing the detailed molecular differences between these two cell types should help in the next generation of targeted therapies, such as nanomedicine.
