Existence, Functional Impairment, and Lung Repair Potential of Endothelial Colony-Forming Cells in Oxygen-Induced Arrested Alveolar Growth

• Published in: Circulation (New York, N.Y.) Vol. 129; no. 21; pp. 2144 - 2157
• Main Authors: Alphonse, Rajesh S, Vadivel, Arul, Fung, Moses, Shelley, William Chris, Critser, Paul John, Ionescu, Lavinia, O’Reilly, Megan, Ohls, Robin K, McConaghy, Suzanne, Eaton, Farah, Zhong, Shumei, Yoder, Merv, Thébaud, Bernard
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD by the American College of Cardiology Foundation and the American Heart Association, Inc 27-05-2014; Lippincott Williams & Wilkins
• Subjects: Animals; Animals, Newborn; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cell Proliferation - drug effects; Cells, Cultured; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endothelial Cells - physiology; Endothelial Cells - transplantation; Fetus; Human Umbilical Vein Endothelial Cells - physiology; Human Umbilical Vein Endothelial Cells - transplantation; Humans; Medical sciences; Mice; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Oxygen - toxicity; Pulmonary Alveoli - drug effects; Pulmonary Alveoli - injuries; Pulmonary Alveoli - surgery; Rats; Rats, Nude; Rats, Sprague-Dawley; Stem Cell Transplantation - methods; Prisoner; Endothelial cell; Carceral environment; Arrest; Growth; Stem cell; Lung; Cardiovascular disease; Potential; Respiratory system; angiogenesis inducing agents; Angiogenesis; Cardiology; Repair; Hypertension; Agent; Lung disease; lung diseases; stem cells; Corrective surgery; Oxygen; Respiratory disease; pulmonary; Colony forming cell; Treatment; Legal aspect; Circulatory system; hypertension, pulmonary
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.114.009124

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.