Babies born with alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) suffer from a lack of oxygenated blood in their systems. Only a lung transplant offers hope for saving their lives.

However, researchers at Cincinnati Children’s Hospital Medicine Center have been studying how ACDMPV develops and now suggest a possible way to treat it after working with a mouse model. Their study (“Endothelial progenitor cells stimulate neonatal lung angiogenesis through FOXF1-mediated activation of BMP9/ACVRL1 signaling”) appears in Nature Communications.

“Pulmonary endothelial progenitor cells (EPCs) are critical for neonatal lung angiogenesis and represent a subset of general capillary cells (gCAPs). Molecular mechanisms through which EPCs stimulate lung angiogenesis are unknown,” write the investigators.

“Herein, we used single-cell RNA sequencing to identify the BMP9/ACVRL1/SMAD1 pathway signature in pulmonary EPCs. BMP9 receptor, ACVRL1, and its downstream target genes were inhibited in EPCs from Foxf1WT/S52F mutant mice, a model of alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Expression of ACVRL1 and its targets were reduced in lungs of ACDMPV subjects.

Vladimir Kalinichenko, MD, PhD, Cincinnati Children’s [Cincinnati Children’s]

“Inhibition of FOXF1 transcription factor reduced BMP9/ACVRL1 signaling and decreased angiogenesis in vitro. FOXF1 synergized with ETS transcription factor FLI1 to activate ACVRL1 promoter. Nanoparticle-mediated silencing of ACVRL1 in newborn mice decreased neonatal lung angiogenesis and alveolarization. Treatment with BMP9 restored lung angiogenesis and alveolarization in ACVRL1-deficient and Foxf1WT/S52F mice.

“Altogether, EPCs promote neonatal lung angiogenesis and alveolarization through FOXF1-mediated activation of BMP9/ACVRL1 signaling.”

“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,” says Vladimir Kalinichenko, MD, PhD, corresponding author and professor in the University of Cincinnati’s department of pediatrics. “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 study describes how the research team sifted through large amounts of single-cell RNA sequencing data collected from more than 7,000 lung cells from mice carrying a gene mutation linked to ACDMPV (a loss-of-function for the gene FOXF1 in humans) and another nearly 6,000 normal lung cells to find the one cell type where the disease creates its devastating results.

The work began by isolating a dozen cell clusters of potential interest. These clusters included alveolar epithelial cells, fibroblasts, club cells, endothelial cells, pericytes, ciliated cells, and myofibroblasts. The initial results prompted the team to focus more closely on activity involving pulmonary endothelial progenitor cells (EPCs) that reside in the inner linings of the lung’s microvascular blood vessels.

Using data from about 800 of these cells, the team found 93 downregulated and 43 upregulated genes in the Foxf1 mutation group compared to the normal group. From this data, the team further reduced the suspects to a critical signaling pathway involving the proteins BMP9, ACVRL1 and SMAD1.

When the FOXF1 protein goes missing or contains one of detrimental mutations, the expression of Acvrl1 is reduced, which in turn reduces expression of downstream target genes. This pathway proves necessary for healthy blood vessel formation in the lungs.

Assessing the importance of this pathway required using a nanoparticle delivery platform developed by the Kalinichenko lab to silence the ACVRL1 protein–but only in the endothelial cells in the lungs of the mice.

The researchers found that adding synthetic bone morphogenetic protein BMP9 to cells that were deficient for functional FOXF1 genes helped re-create the signaling pathway, stimulating Acvrl1 activity, and instructing the lungs to keep making capillaries. The scientists confirmed this through tests in lab cell cultures and in mice.

BMP9 is one of about 20 different such proteins found in humans. Originally discovered to play major roles in bone growth, more recently this class of molecules has been shown to play a variety of roles in development.

Two other related proteins—BMP7 and BMP2—have been approved by the FDA for treating bone growth disorders. But so far, no drug that stimulates BMP9 activity has been approved for human use.

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, notes Kalinichenko. 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.

The treatment eventually might also benefit infants with congenital diaphragmatic hernia (CDH). In these children, gaps in the diaphragm allow other internal organs to crowd into space needed by the lungs. While surgery can repair the hernia, in many cases the lungs struggle to return to a normal pattern of growth.

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