Existence, functional impairment, and lung repair potential of endothelial colony-forming cells in oxygen-induced arrested alveolar growth

Rajesh S. Alphonse, Arul Vadivel, Moses Fung, William Chris Shelley, Paul John Critser, Lavinia Ionescu, Megan O'Reilly, Robin K. Ohls, Suzanne McConaghy, Farah Eaton, Shumei Zhong, Merv Yoder, Bernard Thébaud

Research output: Contribution to journalArticle

76 Scopus citations

Abstract

Background - Bronchopulmonary dysplasia and emphysema are life-threatening diseases resulting from impaired alveolar development or alveolar destruction. Both conditions lack effective therapies. Angiogenic growth factors promote alveolar growth and contribute to alveolar maintenance. Endothelial colony-forming cells (ECFCs) represent a subset of circulating and resident endothelial cells capable of self-renewal and de novo vessel formation. We hypothesized that resident ECFCs exist in the developing lung, that they are impaired during arrested alveolar growth in experimental bronchopulmonary dysplasia, and that exogenous ECFCs restore disrupted alveolar growth. Methods and Results - Human fetal and neonatal rat lungs contain ECFCs with robust proliferative potential, secondary colony formation on replating, and de novo blood vessel formation in vivo when transplanted into immunodeficient mice. In contrast, human fetal lung ECFCs exposed to hyperoxia in vitro and neonatal rat ECFCs isolated from hyperoxic alveolar growth-arrested rat lungs mimicking bronchopulmonary dysplasia proliferated less, showed decreased clonogenic capacity, and formed fewer capillary-like networks. Intrajugular administration of human cord blood-derived ECFCs after established arrested alveolar growth restored lung function, alveolar and lung vascular growth, and attenuated pulmonary hypertension. Lung ECFC colony- and capillary-like network-forming capabilities were also restored. Low ECFC engraftment and the protective effect of cell-free ECFC-derived conditioned media suggest a paracrine effect. Long-term (10 months) assessment of ECFC therapy showed no adverse effects with persistent improvement in lung structure, exercise capacity, and pulmonary hypertension. Conclusions - Impaired ECFC function may contribute to arrested alveolar growth. Cord blood-derived ECFC therapy may offer new therapeutic options for lung diseases characterized by alveolar damage.

Original languageEnglish (US)
Pages (from-to)2144-2157
Number of pages14
JournalCirculation
Volume129
Issue number21
DOIs
StatePublished - May 27 2014

Keywords

  • Angiogenesis inducing agents
  • Hypertension pulmonary
  • Lung diseases
  • Stem cells

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

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    Alphonse, R. S., Vadivel, A., Fung, M., Shelley, W. C., Critser, P. J., Ionescu, L., O'Reilly, M., Ohls, R. K., McConaghy, S., Eaton, F., Zhong, S., Yoder, M., & Thébaud, B. (2014). Existence, functional impairment, and lung repair potential of endothelial colony-forming cells in oxygen-induced arrested alveolar growth. Circulation, 129(21), 2144-2157. https://doi.org/10.1161/CIRCULATIONAHA.114.009124