title: Alveolar epithelial cell therapy with human cord blood-derived hematopoietic progenitor cells.
abstract: The role of umbilical cord blood (CB)-derived stem cell therapy in neonatal lung injury remains undetermined. We investigated the capacity of human CB-derived CD34(+) hematopoietic progenitor cells to regenerate injured alveolar epithelium in newborn mice. Double-transgenic mice with doxycycline (Dox)-dependent lung-specific Fas ligand (FasL) overexpression, treated with Dox between embryonal day 15 and postnatal day 3, served as a model of neonatal lung injury. Single-transgenic non-Dox-responsive littermates were controls. CD34(+) cells (1 × 10(5) to 5 × 10(5)) were administered at postnatal day 5 by intranasal inoculation. Engraftment, respiratory epithelial differentiation, proliferation, and cell fusion were studied at 8 weeks after inoculation. Engrafted cells were readily detected in all recipients and showed a higher incidence of surfactant immunoreactivity and proliferative activity in FasL-overexpressing animals compared with non-FasL-injured littermates. Cord blood-derived cells surrounding surfactant-immunoreactive type II-like cells frequently showed a transitional phenotype between type II and type I cells and/or type I cell-specific podoplanin immunoreactivity. Lack of nuclear colocalization of human and murine genomic material suggested the absence of fusion. In conclusion, human CB-derived CD34(+) cells are capable of long-term pulmonary engraftment, replication, clonal expansion, and reconstitution of injured respiratory epithelium by fusion-independent mechanisms. Cord blood-derived surfactant-positive epithelial cells appear to act as progenitors of the distal respiratory unit, analogous to resident type II cells. Graft proliferation and alveolar epithelial differentiation are promoted by lung injury.
authors.affiliation: Department of Pathology, Women and Infants Hospital, Providence, Rhode Island 02905, USA. mdepaepe@wihri.org
authors.forename: Monique E
authors.initials: ME
authors.lastname: De Paepe
authors.forename: Quanfu
authors.initials: Q
authors.lastname: Mao
authors.forename: Sailaja
authors.initials: S
authors.lastname: Ghanta
authors.forename: Virginia
authors.initials: V
authors.lastname: Hovanesian
authors.forename: James F
authors.initials: JF
authors.lastname: Padbury
mesh_terms: D000281:Administration, Intranasal; D020087:Alu Elements / Q000235:genetics; D056809:Alveolar Epithelial Cells / Q000166:cytology*; D000818:Animals; D000831:Animals, Newborn; D018952:Antigens, CD34 / Q000378:metabolism; D002454:Cell Differentiation; D002459:Cell Fusion; D019070:Cell Lineage; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000166:cytology; D005312:Fetal Blood / Q000166:cytology*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D008168:Lung / Q000166:cytology; D051379:Mice; D020545:Respiratory Mucosa / Q000166:cytology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014020:Tissue Extracts
chemical_list: D018952:Antigens, CD34; D014020:Tissue Extracts