Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a breathing problem a newborn might experience where their skin starts to turn blue from the under-oxygenated blood in their system. It is an extremely rare condition that has been identified in just a few hundred births. At this time, not much can be done to save these children, except for a lung transplant.

Scientists at Cincinnati Children’s Hospital Medical Center are shedding new light on how ACDMPV develops and how to possibly treat it. Their findings were recently published in Nature Communications.

According to the corresponding author, Dr. Vladimir Kalinichenko, “Treatment with BMP9 effectively restored capillary density, improved alveolarization, increased arterial oxygenation, increased expression of BMP9 receptor on the surface of capillary endothelial cells called Acvrl1, and improved survival in the ACDMPV mouse model. The improvements are striking. However, several more research steps are needed before BMP9 therapy could be ready for human clinical trials.”

Isolating a Key Molecular Signaling Pathway

The research team at Cincinnati Children’s analyzed single-cell RNA sequencing data collected from more than 7,000 lung cells from mice carrying a gene mutation linked to ACDMPV and almost 6,000 normal lung cells to figure out what kind of cell was causing the extreme disease symptoms. This gene mutation was a loss of function for the gene FOXF1in humans.

Potential cells of interest included alveolar epithelial cells, fibroblasts, club cells, endothelial cells, pericytes, ciliated cells, and myofibroblasts. Initial results led the team to focus on the cells in the inner lining of the lung’s microvascular blood vessels, known as pulmonary endothelial progenitor cells (EPCs).

The data was further narrowed to determine a critical signaling pathway involving BMP9, ACVRL1 and SMAD1 proteins. When FOXF1 is missing or mutated, ACVRL1 expression goes down. This then reduces the expression of the downstream target genes, a pathway which is critical for healthy blood vessel formation in the lungs.

The Kalinichenko lab assesses this pathway using a nanoparticle delivery platform which they developed to silence the ACVRL1 protein in endothelial lungs cells in mice.

Hope for a Potential Treatment

The team discovered that by adding synthetic bone morphogenetic protein BMP9 to cells deficient in functional FOXF1 genes, they were able to restore the ACVRL1 activity pathway. This allowed the lung to keep making capillaries, as confirmed in cell cultures and in mice.

BMP9 was originally found to play a role in bone growth, but recent discoveries such as this one show it plays multiple roles in development. Similar proteins, such as BMP7 and BMP2, have been approved for treating bone growth disorders in human, but no BMP9-stimulating drugs have been approved for use in humans.

According to Kalinichenk, “If a safe BMP9 ‘agonist’ or synthetic BMP9 molecule suitable for human use can be developed, it could become more than a treatment strictly for ACDMPV. It might also stimulate blood vessel growth that gets hampered by bronchopulmonary dysplasia (BPD)–a complication of premature birth that occurs in about 10,000 to 15,000 babies a year. While most infants survive this condition, early interventions that could spur lung damage repair could help prevent increased risks of asthma and lung infections later in life.”

Related Reagents

If you are working on a similar research project, you might be interested in some of our reagents related to bone or lung research, including:

• Bone Cell Lines from University of Missouri – Kansas City
• BMP Responsive Reporter Osteoblast Cell Line from Indian Institute of Technology Kanpur
• Heparan Sulfate Mutant Mouse Lung Endothelial Cell Lines from University of Georgia
• Human Bronchial Epithelial Cell Line (BEAS-2B) from the National Cancer Institute/NIH
• Canine Osteosarcoma Cell Lines from University of Minnesota, Twin Cities
• Osteopontin Antibodies from Rutgers University
• Smad6 Lentivirus