05 February 2018 by Alexi Crosby

A role for the bone morphogenetic protein type 2 receptor (BMPR2) in differentiation of the common myeloid progenitor lineage in mice and humans

Rationale

There is increasing evidence of 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 mice and humans.

Methods

Mx1-cre mice were crossed with bmpr2flox/floxmice. At approximately 8 weeks old cre-recombinase was induced with polyinosinic-polycytidylic acid (Poly I:C). Control mice were induced. Approximately 16 weeks post-induction mice underwent right-heart catheterisation, exsanguination and tissue was removed for analysis. Mouse data are presented as mean ±SEM. In a large cohort of PAH patients with (n=160) and without (n=831) BMPR2 mutations blood count indices were analysed. Data presented as median [IQR].

Results

16 weeks post-induction of Mx1-cre/bmpr2flox/floxmice we observed an increase (p<0.05) in red blood cells (x106/mm3) (12.7±0 vs. 12.1±0.2), haematocrit (%) (64.8±0.7 vs.62.6±1) and haemoglobin (g/dl) (16±0.9 vs. 15.4±0.2) compared with bmpr2flox/floxmice. An increase in circulating monocytes (x103/mm3) was also observed (p<0.05) (0.4±0.05 vs. 0.3±0.05). There was an increase (p<0.05) in megakaryocytes in the femurs (80±10 vs. 17±5) and an increase (p<0.01) in the ratio of spleen/body weight (0.003±0.0001 vs. 0.002±0.0001) in Mx1-cre/bmpr2flox/flox mice. Right ventricular systolic pressures were similar in both groups. In PAH patients differences (p<0.05) were seen in haemoglobin (BMPR2 mutation: 162g/L [151.75 – 173]) vs. no mutation: 150g/L [135 – 163]), haematocrit (0.48 [0.45 - 0.52] vs. 0.44 [0.41 - 0.48]) and white blood cells (8.8 [7.3 - 10.4] vs. 8.11 [6.77 - 9.61]).

Conclusions

We have identified a role for bmpr2 in the differentiation of the mouse myeloid lineage, which was also confirmed in patients with BMPR2 mutations and PAH. BMPR2 appears particularly important in the differentiation of megakaryocyte-erythrocyte lineage.

Key Contributors

Alexi Crosby1, Charaka Hadinnapola1, Emily Groves1, Stephen Moore1, Benjamin Dunmore1, Mark Southwood2, 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 Gräf3, Mark Toshner1, Nicholas Morrell1 1 Department of Medicine, Cambridge University, 2 Department of Pathology, Papworth Hospital, 3 NIHR BioResource – Rare Diseases Consortium and UK National Cohort Study of Idiopathic and Heritable PAH


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