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


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.
From the Department of Pediatrics, Women and Children's Health Research Institute, Cardiovascular Research Center and Pulmonary Research Group, University of Alberta, Edmonton, Canada (R.S.A., M.F., L.I. M.O., F.E.); Ottawa Hospital Research Institute, Regenerative Medicine Program, Sprott Center for Stem Cell Research, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada (A.V., S.Z., B.T.); Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN (W.C.S., P.J.C., M.Y.); and Department of Pediatrics, University of New Mexico, Albuquerque, NM (R.K.O., S.M.).
Rajesh S
RS
Alphonse
From the Department of Pediatrics, Women and Children's Health Research Institute, Cardiovascular Research Center and Pulmonary Research Group, University of Alberta, Edmonton, Canada (R.S.A., M.F., L.I. M.O., F.E.); Ottawa Hospital Research Institute, Regenerative Medicine Program, Sprott Center for Stem Cell Research, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada (A.V., S.Z., B.T.); Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN (W.C.S., P.J.C., M.Y.); and Department of Pediatrics, University of New Mexico, Albuquerque, NM (R.K.O., S.M.).
Arul
A
Vadivel
From the Department of Pediatrics, Women and Children's Health Research Institute, Cardiovascular Research Center and Pulmonary Research Group, University of Alberta, Edmonton, Canada (R.S.A., M.F., L.I. M.O., F.E.); Ottawa Hospital Research Institute, Regenerative Medicine Program, Sprott Center for Stem Cell Research, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada (A.V., S.Z., B.T.); Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN (W.C.S., P.J.C., M.Y.); and Department of Pediatrics, University of New Mexico, Albuquerque, NM (R.K.O., S.M.).
Moses
M
Fung
From the Department of Pediatrics, Women and Children's Health Research Institute, Cardiovascular Research Center and Pulmonary Research Group, University of Alberta, Edmonton, Canada (R.S.A., M.F., L.I. M.O., F.E.); Ottawa Hospital Research Institute, Regenerative Medicine Program, Sprott Center for Stem Cell Research, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada (A.V., S.Z., B.T.); Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN (W.C.S., P.J.C., M.Y.); and Department of Pediatrics, University of New Mexico, Albuquerque, NM (R.K.O., S.M.).
William Chris
WC
Shelley
From the Department of Pediatrics, Women and Children's Health Research Institute, Cardiovascular Research Center and Pulmonary Research Group, University of Alberta, Edmonton, Canada (R.S.A., M.F., L.I. M.O., F.E.); Ottawa Hospital Research Institute, Regenerative Medicine Program, Sprott Center for Stem Cell Research, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada (A.V., S.Z., B.T.); Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN (W.C.S., P.J.C., M.Y.); and Department of Pediatrics, University of New Mexico, Albuquerque, NM (R.K.O., S.M.).
Paul John
PJ
Critser
From the Department of Pediatrics, Women and Children's Health Research Institute, Cardiovascular Research Center and Pulmonary Research Group, University of Alberta, Edmonton, Canada (R.S.A., M.F., L.I. M.O., F.E.); Ottawa Hospital Research Institute, Regenerative Medicine Program, Sprott Center for Stem Cell Research, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada (A.V., S.Z., B.T.); Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN (W.C.S., P.J.C., M.Y.); and Department of Pediatrics, University of New Mexico, Albuquerque, NM (R.K.O., S.M.).
Lavinia
L
Ionescu
From the Department of Pediatrics, Women and Children's Health Research Institute, Cardiovascular Research Center and Pulmonary Research Group, University of Alberta, Edmonton, Canada (R.S.A., M.F., L.I. M.O., F.E.); Ottawa Hospital Research Institute, Regenerative Medicine Program, Sprott Center for Stem Cell Research, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada (A.V., S.Z., B.T.); Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN (W.C.S., P.J.C., M.Y.); and Department of Pediatrics, University of New Mexico, Albuquerque, NM (R.K.O., S.M.).
Megan
M
O'Reilly
From the Department of Pediatrics, Women and Children's Health Research Institute, Cardiovascular Research Center and Pulmonary Research Group, University of Alberta, Edmonton, Canada (R.S.A., M.F., L.I. M.O., F.E.); Ottawa Hospital Research Institute, Regenerative Medicine Program, Sprott Center for Stem Cell Research, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada (A.V., S.Z., B.T.); Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN (W.C.S., P.J.C., M.Y.); and Department of Pediatrics, University of New Mexico, Albuquerque, NM (R.K.O., S.M.).
Robin K
RK
Ohls
From the Department of Pediatrics, Women and Children's Health Research Institute, Cardiovascular Research Center and Pulmonary Research Group, University of Alberta, Edmonton, Canada (R.S.A., M.F., L.I. M.O., F.E.); Ottawa Hospital Research Institute, Regenerative Medicine Program, Sprott Center for Stem Cell Research, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada (A.V., S.Z., B.T.); Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN (W.C.S., P.J.C., M.Y.); and Department of Pediatrics, University of New Mexico, Albuquerque, NM (R.K.O., S.M.).
Suzanne
S
McConaghy
From the Department of Pediatrics, Women and Children's Health Research Institute, Cardiovascular Research Center and Pulmonary Research Group, University of Alberta, Edmonton, Canada (R.S.A., M.F., L.I. M.O., F.E.); Ottawa Hospital Research Institute, Regenerative Medicine Program, Sprott Center for Stem Cell Research, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada (A.V., S.Z., B.T.); Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN (W.C.S., P.J.C., M.Y.); and Department of Pediatrics, University of New Mexico, Albuquerque, NM (R.K.O., S.M.).
Farah
F
Eaton
From the Department of Pediatrics, Women and Children's Health Research Institute, Cardiovascular Research Center and Pulmonary Research Group, University of Alberta, Edmonton, Canada (R.S.A., M.F., L.I. M.O., F.E.); Ottawa Hospital Research Institute, Regenerative Medicine Program, Sprott Center for Stem Cell Research, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada (A.V., S.Z., B.T.); Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN (W.C.S., P.J.C., M.Y.); and Department of Pediatrics, University of New Mexico, Albuquerque, NM (R.K.O., S.M.).
Shumei
S
Zhong
From the Department of Pediatrics, Women and Children's Health Research Institute, Cardiovascular Research Center and Pulmonary Research Group, University of Alberta, Edmonton, Canada (R.S.A., M.F., L.I. M.O., F.E.); Ottawa Hospital Research Institute, Regenerative Medicine Program, Sprott Center for Stem Cell Research, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada (A.V., S.Z., B.T.); Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN (W.C.S., P.J.C., M.Y.); and Department of Pediatrics, University of New Mexico, Albuquerque, NM (R.K.O., S.M.).
Merv
M
Yoder
From the Department of Pediatrics, Women and Children's Health Research Institute, Cardiovascular Research Center and Pulmonary Research Group, University of Alberta, Edmonton, Canada (R.S.A., M.F., L.I. M.O., F.E.); Ottawa Hospital Research Institute, Regenerative Medicine Program, Sprott Center for Stem Cell Research, Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada (A.V., S.Z., B.T.); Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Division of Neonatal-Perinatal Medicine, Indiana University School of Medicine, Indianapolis, IN (W.C.S., P.J.C., M.Y.); and Department of Pediatrics, University of New Mexico, Albuquerque, NM (R.K.O., S.M.). bthebaud@ohri.
Bernard
B
Thébaud
D000818:Animals; D000831:Animals, Newborn; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology* / Q000637:transplantation; D005333:Fetus; D061307:Human Umbilical Vein Endothelial Cells / Q000502:physiology / Q000637:transplantation; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D010100:Oxygen / Q000633:toxicity*; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000293:injuries / Q000601:surgery*; D051381:Rats; D011923:Rats, Nude; D017207:Rats, Sprague-Dawley; D033581:Stem Cell Transplantation / Q000379:methods*
D010100:Oxygen
angiogenesis inducing agents; hypertension, pulmonary; lung diseases; stem cells