Reply: Expanded Role for Bone Marrow–derived Hematopoietic Stem and Progenitor Cells in Pulmonary Arterial Hypertension

From the Authors:

We agree with Asosingh and colleagues that there are now considerable data to indicate that the hematopoietic compartment of bone marrow contributes to the pathophysiology of pulmonary arterial hypertension (PAH). Initial direct evidence of this was provided by their seminal work, and our data further expanded and clarified their findings (1, 2). It is important to point out here that our data do not suggest a diminished role for pulmonary vascular cells in PAH pathogenesis; they simply highlight the fact that bone marrow cells (BMC) are more important in PAH pathogenesis than previously believed.

The exact role of BMC in PAH has remained elusive in part because of (1) use of animal models such as Sugen, monocrotaline, or hypoxia, in which both BMC and microvascular cells were exposed to the stimuli, and thus precise dissection of the relative roles of BMC from microvascular cells could not be done; and (2) the short-term duration of the experimental design. For example, although monocrotaline or hypoxia can lead to rapid development of PAH in rodents, this does not mimic the long-term course of PAH in humans, in which the disease develops slowly over many years. Thus, genetic models of PAH are key to further delineating the role of BMC in PAH.

This work (Yan and colleagues [2] and Asosingh and colleagues [1]) also focuses on the potential of BMC as a therapeutic option in PAH. It is well known that PAH is refractory to most of the conventional pharmacological therapies. Lung transplantation effectiveness is limited owing to the number of donor organs available and the risks for graft rejection. Our combined work would suggest that better delineation of the role of BMCs in PAH, in particular BMCs of hematopoietic lineage such as hematopoietic stem cells, is needed to further clarify their potential use as a legitimate therapeutic approach. This is an important translational question with potential to affect patient treatment, because allogeneic bone marrow transplantation has been done for a long time for a number of hematological and genetic disorders, and the protocols are well established.