Bone marrow–derived cells contribute to the pathogenesis of pulmonary arterial hypertension
L Yan, X Chen, M Talati, BW Nunley… - American Journal of …, 2016 - atsjournals.org
American Journal of Respiratory and Critical Care Medicine, 2016•atsjournals.org
Rationale: Pulmonary arterial hypertension (PAH) is a progressive lung disease of the
pulmonary microvasculature. Studies suggest that bone marrow (BM)-derived circulating
cells may play an important role in its pathogenesis. Objectives: We used a genetic model of
PAH, the Bmpr2 mutant mouse, to study the role of BM-derived circulating cells in its
pathogenesis. Methods: Recipient mice, either Bmpr2 R899X mutant or controls, were
lethally irradiated and transplanted with either control or Bmpr2 R899X BM cells. Donor cells …
pulmonary microvasculature. Studies suggest that bone marrow (BM)-derived circulating
cells may play an important role in its pathogenesis. Objectives: We used a genetic model of
PAH, the Bmpr2 mutant mouse, to study the role of BM-derived circulating cells in its
pathogenesis. Methods: Recipient mice, either Bmpr2 R899X mutant or controls, were
lethally irradiated and transplanted with either control or Bmpr2 R899X BM cells. Donor cells …
Rationale: Pulmonary arterial hypertension (PAH) is a progressive lung disease of the pulmonary microvasculature. Studies suggest that bone marrow (BM)-derived circulating cells may play an important role in its pathogenesis.
Objectives: We used a genetic model of PAH, the Bmpr2 mutant mouse, to study the role of BM-derived circulating cells in its pathogenesis.
Methods: Recipient mice, either Bmpr2R899X mutant or controls, were lethally irradiated and transplanted with either control or Bmpr2R899X BM cells. Donor cells were traced in female recipient mice by Y chromosome painting. Molecular and function insights were provided by expression and cytokine arrays combined with flow cytometry, colony-forming assays, and competitive transplant assays.
Measurements and Main Results: We found that mutant BM cells caused PAH with remodeling and inflammation when transplanted into control mice, whereas control BM cells had a protective effect against the development of disease, when transplanted into mutant mice. Donor BM-derived cells were present in the lungs of recipient mice. Functional and molecular analysis identified mutant BM cell dysfunction suggestive of a PAH phenotype soon after activation of the transgene and long before the development of lung pathology.
Conclusions: Our data show that BM cells played a key role in PAH pathogenesis and that the transplanted BM cells were able to drive the lung phenotype in a myeloablative transplant model. Furthermore, the specific cell types involved were derived from hematopoietic stem cells and exhibit dysfunction long before the development of lung pathology.
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