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Division of Thoracic Surgery, Toronto General Hospital, 200 Elizabeth St, 9N-949, Toronto, Ontario, M5G 2C4, Canada
(Email: tom.waddell{at}uhn.on.ca).
I read with interest the report by Yoshida and colleagues [1].
Cellular therapy for lung disease shows great promise, especially in the treatment of pulmonary arterial hypertension (PAH). Recent important advances have been made in our understanding both of the pathogenesis and treatment of this devastating disease. Gene hunting efforts in familial PAH have identified loss-of-function mutations in the bone morphogenetic protein-2 (BMP2) gene, a defect also seen in many patients with idiopathic PAH [2]. The BMP2 gene enhances resistance to inflammatory stress in both endothelial cells and circulating endothelial progenitors, an effect not seen in the circulating endothelial progenitor populations of PAH patients [3]. Heterozygous mutations in BMP2R enhance the inflammatory response and endothelial injury seen in standard monocrotaline models of PAH [4].
Cellular therapy for PAH began with the work of Campbell and colleagues [5, 6] in their attempts to use cells simply as vectors for gene transfer [5, 6]. Initially examining endothelial nitric oxide synthase (eNOS) and then vascular endothelial growth factor (VEGF), Ang-1, or adrenomedullin as angiogenic genes, these and other investigators subsequently used bone marrow-derived "endothelial progenitor cells." For some time there was great enthusiasm that these cells themselves could contribute to the endothelial lining [6, 7]. In these later reports, cells were cultured for a period of time in vitro to allow time for gene transfer, but there were clear therapeutic benefits of the mock transfected cells as well. Generalized skepticism regarding the "transdifferentiation" phenomenon of bone marrow-derived cells in general, and the robustness of early outgrowth "endothelial progenitor cells" in particular, has dampened enthusiasm for vascular repair by the cells themselves. Attention has returned to paracrine benefits toward the endogenous vasculature.
In the current report by Yoshida and colleagues [1], unfractionated, untransfected, bone marrow mononuclear cells demonstrated significant benefit in a murine model of PAH. The VEGF levels were substantively increased by this cell therapy, and the benefits of the cell therapy were blocked by a VEGF inhibitor. Surprisingly, the cells could not be detected at any time point in the lungs. Has the pendulum swung so far? Not only do bone marrow cells not incorporate into the vasculature, they do not need to exist at all to have substantial benefit. There would seem to be three possibilities. First, the technique of cell detection may have been flawed or insufficiently sensitive. No positive control or alternate technique was used. Second, the authors did not examine other locations; perhaps these cells have homed to the bone marrow but are secreting significant amounts of VEGF from a remote location. Third, the transient delivery of bone marrow cells may induce other recipient cells to begin secretion of large amounts of VEGF, which alters the subsequent course of PAH. All three are testable hypotheses, and it is to be hoped that this group continues to explore this phenomenon.
The simplicity of the current protocol, without transfection or ex-vivo culture, is appealing. However, those considering clinical translation should be chastened by the huge cell doses involved. Yoshida and colleagues [1] used 10 million cells in a mouse compared with Stewart's group who used 1 million in a rat. This might roughly translate to 21 billion cells in a human. It is doubtful that such large numbers of fresh autologous bone marrow cells could be obtained, processed, or safely delivered.
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