Pulmonary vascular disease in mice xenografted with human BM progenitors from patients with pulmonary arterial hypertension

Abstract

Hematopoietic myeloid progenitors released into the circulation are able to promote vascular remodeling through endothelium activation and injury. Endothelial injury is central to the development of pulmonary arterial hypertension (PAH), a proliferative vasculopathy of the pulmonary circulation, but the origin of vascular injury is unknown. In the present study, mice transplanted with BM-derived IntroductionVascular endothelial injury with in situ thrombi is a typical pathologic finding in pulmonary arterial hypertension (PAH). Progressive disease is characterized by complex vascular malformations composed of disorganized proliferating monoclonal endothelial cells with neointima formation. 1 Although endothelial injury is hypothesized to account for the origins of PAH, the underlying mechanism of the vascular injury is unknown. Hematopoietic myeloid proangiogenic progenitors play a central role in endothelial injury and repair. We and others have reported that distinct 2-4 or indolent 5 myeloid abnormalities are present in the BM of the majority, if not all, of patients with PAH and even in unaffected family members 5 in familial cases of the disease. These findings and the unexplained high incidence of PAH among patients with myeloproliferative diseases 6,7 suggest a myelopulmonary pathophysiologic link. In support of this concept, competent hematopoietic progenitors are required for disease development in the monocrotaline-or hypoxia-induced murine models of pulmonary hypertension, and BM transplantation can transfer disease to healthy naive mice. 8 In contrast to developmental origins of blood cells and vascular endothelium from the common hemangioblast, hematopoietic stem cells in the adult do not differentiate into endothelium, but rather promote postnatal angiogenesis and homeostasis in a paracrine fashion. [9][10][11][12] In the hierarchy of adult hematopoietic stem cell differentiation, a small pool of pluripotent, BMresident stem cells exhibit self-renewal and long-term survival. 13 These stem cells proliferate and differentiate into relatively shortlived multipotent progenitors that give rise to common lymphoid and common myeloid progenitors. Common lymphoid progenitors further differentiate into B-or T cell-committed precursors. The common myeloid progenitors proliferate and differentiate into bipotent common erythroid/megakaryocyte progenitors and into multipotent monocyte/granulocyte progenitors. These lineagerestricted myeloid progenitors differentiate into mature blood cells via unilineage-committed intermediate precursors. The hierarchy of proliferation and differentiation is at each bifurcation strictly regulated by lineage-specific transcription factors. 13 In the BM, the cell-surface glycoprotein CD133 is highly expressed on immature progenitors, allowing CD133 expression to define the population of hematopoietic progenitors. Functional analysis of human BM-derived CD133 ϩ cells indicates that this fraction is enriched in primitive multilineage hematopoietic stem cells. 14 Early outgrowth pro...

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

“…23 Consistent with this finding, CAV-1 KO CMP was also skewed toward the erythroid-megakaryocyte lineage independent of hypoxia exposure. Interestingly, while the opposite (increased granulocyte-monocyte differentiation) was observed in WT mice with hypoxia-induced PH, BM from these mice was unable to transfer the disease.…”

“…22 BM hematopoietic stem cells (HSCs) from patients with a CAV-1 mutation that were engrafted in nonobese diabetic severe combined immunodeficiency mice led to severe pulmonary vascular remodeling and RV hypertrophy. 23 Data from other animal models further support the essential role for CAV-1 in PH. Monocrotaline-induced PH in rats is associated with disruption of endothelial CAV-1 rafts, and restoration of CAV-1 function in this model inhibited the development of PH and RV hypertrophy.…”

“…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. Here, we used the immunocompetent CAV-1 KO mouse model to study whether engraftment of healthy BM in CAV-1 KO mice prevents pulmonary vascular remodeling and development of right heart disease.…”

“…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.…”

“…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. 23 Pulmonary vascular disease and RV remodeling are key characteristics of PH, but the connection between these 2 processes and whether or not healthy BM can inhibit maladaptation of the right heart have not been addressed.…”