Bone Marrow–derived Cells Contribute to the Pathogenesis of Pulmonary Arterial Hypertension

Abstract

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.

Translational Advances in the Field of Pulmonary Hypertension Molecular Medicine of Pulmonary Arterial Hypertension. From Population Genetics to Precision Medicine and Gene Editing

“…There is evidence from several groups that bone marrow cells alone are sufficient to drive PAH, including our finding that control bone marrow-derived stem cells can reduce the PAH phenotype when transplanted into lethally irradiated Bmpr2 mutant mice (63,64). This suggests the future possibility of autologous bone marrow transplantation after edited correction of stem cells as a therapeutic possibility; that is, correction of the mutation from the stem cells of a BMPR2 mutation carrier with PAH could be a therapeutic approach (Figure 3) (64). However, this is technically challenging for a variety of reasons, including the need for high efficiency, the need to avoid off-target effects, and the need for high speed to avoid genomic instability or terminal differentiation of stem cells.…”

Bone marrow transplantation prevents right ventricle disease in the caveolin-1–deficient mouse model of pulmonary hypertension

“…23,29,30 Engraftment of serotonin 2B receptordeficient BM in WT mice protected against the development of hypoxia-induced pulmonary vascular remodeling and elevation of RVSP in mice. 29 In a Bmpr2 mutant model that spontaneously developed PH without RV remodeling, pulmonary vascular remodeling and elevation of RVSP were shown to be dependent on the BM.…”

“…29 In a Bmpr2 mutant model that spontaneously developed PH without RV remodeling, pulmonary vascular remodeling and elevation of RVSP were shown to be dependent on the BM. 30 Also, xenograft studies with BM isolated from patients showed that PAH BM induced pathological RV hypertrophy. 23 In a prior study, BM from patients with germline CAV-1 mutation led to a more severe phenotype in the xenografted mice.…”

“…In a Bmpr2 mutant model that spontaneously developed PH without right ventricular remodeling, pulmonary vascular remodeling and elevation of RVSP were dependent on the BM. 30 Xenotransplantation of PH patient BM HSCs into nonobese diabetic severe combined immunodeficiency mice induced pulmonary angiogenic remodeling and RV hypertrophy. 23 Moreover, HSCs in the BM of PH patients were skewed in the myeloid differentiation toward megakaryocyte-erythroid lineage.…”

Precision medicine and personalising therapy in pulmonary hypertension: seeing the light from the dawn of a new era

“…More recent studies have confirmed the ability of BMPR2 gene therapy to improve PAH in animal models by increasing Smad1/5/8 signalling and possibly by increasing nitric oxide production in human pulmonary endothelial cells [85]. YAN et al [86] showed that myeloablative radiation followed by transplantation of donor stem cells from mice with normal BMPR2 into mice with BMPR2 mutations prevented the development of PH. Although these pre-clinical data are promising, there are likely to be significant challenges in translating BMPR2 gene therapy to humans with our current limitations in vector delivery to the pulmonary endothelium, immunogenicity and uncertainty regarding whether increasing BMPR-II expression results in sustainable long-term improvements in PAH.…”