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Pulmonary Arterial Hypertension: A Stem Cell Hypothesis

  • Chapter
Lung Stem Cells in the Epithelium and Vasculature

Part of the book series: Stem Cell Biology and Regenerative Medicine ((STEMCELL))

Abstract

Pulmonary arterial hypertension (PAH) is caused by precapillary arteriolar vasoconstriction and/or alterations of the anatomy of the small lung vessels, also known as pulmonary vascular remodeling. While the muscularization of the small pulmonary arteries is a physiological and reversible response to chronic hypoxia, the vascular changes known as “angioproliferative” are irreversible and refractory to therapy. Our hypothesis of the “quasi-malignancy” of the complex and multicellular vascular lesions leaves room for stem cell niches and seeding of the lung vessels with precursor or stem cells released from the bone marrow.

In this chapter we introduce the concept that the development and progression of the angio-obliterative lung vascular lesions is part of a “wound healing process gone awry” and depends on the growth of apoptosis-resistant stem—or stem-like cells. Indeed, immunohistochemistry indicates that cells which express stem cell markers are present in the lung vessels from rats that developed severe angio-obliterative PAH in the Sugen 5416/chronic hypoxia (Su/Hx) model and in the lungs from patients with severe PAH. Acceptance of a stem cell hypothesis of severe angio-obliterative PAH leads to the conclusion that effective treatment of severe, angio-obliterative PAH would require strategies directed towards differentiation of lung vascular stem cells.

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Abbreviations

ADAMTS1:

A disintegrin and metalloproteinase with thrombospondin motifs 1

BMPR2:

Bone morphogenic protein receptor 2

CD133:

Cluster of differentiation 133 (aka prominin 1)

CD146:

Cluster of differentiation 146 (aka melanoma cell adhesion molecule (MCAM))

EnMT:

Endothelial mesenchymal transition

HIF:

Hypoxia-inducible factor

HOXC6/8:

Homeobox C6/8

IPAH:

Idiopathic pulmonary hypertension

IPSC:

Induced pluripotent stem cells

Muse:

Multilineage differentiating stress-enduring cells

NG2:

Neural/glial antigen 2

PAH:

Pulmonary arterial hypertension

PDGFR:

Platelet-derived growth factor receptor

Sca-1:

Ly-6 A/E

VEGF:

Vascular endothelial growth factor

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Acknowledgments

Some of the experimental work on which this chapter is based was supported by funding from the Victoria Johnson Center for Lung Research at Virginia Commonwealth University. Excellent immunohistochemistry was performed by Mrs. Daniela Farkas.

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Authors and Affiliations

  1. Department of Environmental and Occupational Health, Florida International University, Miami, FL, USA

    Quentin Felty

  2. Department of Respirology, Chiba University, Chiba, Japan

    Seiijiro Sakao

  3. Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA

    Norbert F. Voelkel

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  1. Quentin Felty
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  2. Seiijiro Sakao
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  3. Norbert F. Voelkel
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Correspondence to Norbert F. Voelkel .

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Editors and Affiliations

  1. Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, California, USA

    Amy Firth

  2. Department of Medicine, The Univsersity of Arizona, Tucson, Arizona, USA

    Jason X.-J. Yuan

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Felty, Q., Sakao, S., Voelkel, N.F. (2015). Pulmonary Arterial Hypertension: A Stem Cell Hypothesis. In: Firth, A., Yuan, JJ. (eds) Lung Stem Cells in the Epithelium and Vasculature. Stem Cell Biology and Regenerative Medicine. Springer, Cham. https://doi.org/10.1007/978-3-319-16232-4_16

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