Cells from the bone marrow participate in the development of pulmonary arterial hypertension (PAH), and they can also protect against it, according to new findings from a team of Vanderbilt University Medical Center investigators.
It was known that bone marrow-derived cells are present in the lungs of patients with PAH, but it was unclear if the cells had a role in the disease or were simply “bystanders” to an ongoing disease process, said Rizwan Hamid, M.D., Ph.D., associate professor of Pediatrics.
The findings, published in the American Journal of Respiratory and Critical Care Medicine, suggest that it may one day be possible to treat PAH with bone marrow transplants.
“This is important because pulmonary arterial hypertension is a really bad disease,” Hamid said. “It’s progressive and fatal. There are no good treatment options for patients.”
In PAH, the blood vessels in the lungs narrow, causing increased pressure. This makes it harder for the heart to pump blood through the lungs and eventually leads to heart failure. The disorder often results from genetic mutations — either inherited or sporadic — but the molecular mechanisms that cause the disease are not known, Hamid said.
The gene most commonly mutated in inherited PAH is the bone morphogenetic protein receptor 2 (BMPR2). Hamid worked with colleagues, including James West, Ph.D., associate professor of Medicine, to study PAH in a genetic mouse model of the disease. The mice express a mutant BMPR2 and develop PAH.
To explore the role of bone marrow in PAH, the investigators performed a series of bone marrow transplants using normal and BMPR2-mutant mice.
They found that mutant bone marrow caused PAH, with cellular remodeling and inflammation, when it was transplanted into normal mice. Normal bone marrow had a protective effect against PAH when it was transplanted into mutant mice.
The researchers tracked chromosomes in the transplanted bone marrow to confirm that donor bone marrow cells were present in the lungs of the recipient mice. Their studies demonstrated that the bone marrow cells involved in PAH are hematopoietic stem cells.
“Who would have thought that a lung disease is being affected by the cells that are part of the hematologic system, not the pulmonary system,” Hamid said.
The findings suggest that bone marrow transplantation may be a viable treatment option for PAH. Hamid and his colleagues will continue to explore this idea in mouse models, with a long-term goal of launching clinical trials in patients.
They also are exploring the potential for “editing” the faulty gene in bone marrow stem cells, so that a patient’s own cells could be used for transplant.
“We’re envisioning a treatment scenario where we take out the bone marrow cells of patients with PAH, fix the mutant gene, and then transplant the cells back into the patient,” Hamid said. “Then there would be no worries about rejection, graft-versus-host disease or other post-transplant problems.”
The findings add to Vanderbilt’s successes in the area of pulmonary hypertension.
“Vanderbilt’s pulmonary hypertension program is number one in the world,” Hamid said. “Fundamental discoveries about pulmonary hypertension have been made here, which gave us the benefit of great collaborators who can think outside the box and provide important feedback.”
Co-authors of the current study include Ling Yan, Ph.D., Xinping Chen, Ph.D., Megha Talati, Ph.D., Bethany Nunley, Santhi Gladson, Tom Blackwell, Joy Cogan, Ph.D., Eric Austin, M.D., MSCI, Ferrin Wheeler, Ph.D., and James Loyd, M.D. The research was supported by a grant from the National Heart, Lung and Blood Institute (HL102020).