04 February 2019 by Alexi Crosby

A role for bone morphogenetic protein type 2 receptor in the differentiation of the myeloid lineage in humans and mice

Rationale:

Increasing evidence suggests a link between abnormalities in the myeloid cell lineage and pulmonary arterial hypertension (PAH). Heterozygous mutations in the gene encoding the bone morphogenetic protein type 2 receptor (BMPR2) are the most common genetic cause of PAH. We sought to characterise the impact of the genetic loss of BMPR2 in the myeloid lineage in humans and mice.

Methods:

In a large cohort of PAH patients with (n=160) and without (n=831) BMPR2 mutations, blood count indicies were analysed. Mx1-cre mice were crossed with bmpr2flox/flox mice. Cre-recombinase was induced with polyinosinic-polycytidylic acid (Poly I:C). 12 weeks post-induction mice underwent right-heart catheterisation, exsanguination and tissue removal.

Results:

12 weeks after induction of cre-recombinase we observed significant increases in red blood cells, haematocrit and haemoglobin in Mx1-cre/bmpr2flox/flox mice compared with bmpr2flox/flox mice (p<0.05). A significant increase in circulating monocytes, megakaryocytes in the femurs (p<0.05) and spleen weight/body weight (p<0.01) were also observed. During right heart catheterisation right ventricular systolic pressures were similar in both groups. PAH patients with a BMPR2 mutation had significant increases (P<0.05) in haemoglobin, haematocrit and white blood cells.

Conclusion:

We have identified a role for bmpr2 in the differentiation of the human and mouse haematopoeitic system. Similarities between PAH patients with a mutation in BMPR2 and mice with bmpr2 knocked out of the myeloid lineage were observed. However, more work is required to determine the exact contribution of BMPR2 deficient bone marrow to the development of PAH.

Rapid-Fire presentation

Key Contributors

Alexi Crosby 1, Charaka Hadinnapola 1, Emily Groves 1, Stephen Moore 1, Benjamin Dunmore 1, Mark Southwood 2, Marta Bleda, Matthias Haimel, Nicholas Screaton, Andrew J. Swift, Peter Dorfmüller, Stephen D. Preston, Jules Hernandez-Sanchez, Jennifer Martin, Carmen Treacy, Katherine Yates, Harm Bogaard, Colin Church, Gerry Coghlan, Robin Condliffe, Paul A. Corris, Simon R. Gibbs, Barbara Girerd, Simon Holden, Marc Humbert, David G. Kiely, Allan Lawrie, Rajiv D. Machado, Robert MacKenzie Ross, Shahin Moledina, David Montani, Michael Newnham, Andrew J. Peacock, Joanna Pepke-Zaba, Paula J. Rayner-Matthews, Olga Shamardina, Florent Soubrier, Laura Southgate, Jay Suntharalingam, Richard C. Trembath, Anton Vonk Noordegraaf, Martin R. Wilkins, Stephen J. Wort, John Wharton, Stefan Gräf 3, Mark Toshner 1, Nicholas Morrell 1


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