title: The Effect of Gender on Mesenchymal Stem Cell (MSC) Efficacy in Neonatal Hyperoxia-Induced Lung Injury.
abstract: BACKGROUND
  Mesenchymal stem cells (MSC) improve alveolar and vascular structures in experimental models of bronchopulmonary dysplasia (BPD). Female MSC secrete more anti-inflammatory and pro-angiogenic factors as compared to male MSC. Whether the therapeutic efficacy of MSC in attenuating lung injury in an experimental model of BPD is influenced by the sex of the donor MSC or recipient is unknown. Here we tested the hypothesis that female MSC would have greater lung regenerative properties than male MSC in experimental BPD and this benefit would be more evident in males.
  
  
  OBJECTIVE
  To determine whether intra-tracheal (IT) administration of female MSC to neonatal rats with experimental BPD has more beneficial reparative effects as compared to IT male MSC.
  
  
  METHODS
  Newborn Sprague-Dawley rats exposed to normoxia (RA) or hyperoxia (85% O2) from postnatal day (P) 2- P21 were randomly assigned to receive male or female IT bone marrow (BM)-derived green fluorescent protein (GFP+) MSC (1 x 106 cells/50 μl), or Placebo on P7. Pulmonary hypertension (PH), vascular remodeling, alveolarization, and angiogenesis were assessed at P21. PH was determined by measuring right ventricular systolic pressure (RVSP) and pulmonary vascular remodeling was evaluated by quantifying the percentage of muscularized peripheral pulmonary vessels. Alveolarization was evaluated by measuring mean linear intercept (MLI) and radial alveolar count (RAC). Angiogenesis was determined by measuring vascular density. Data are expressed as mean ± SD, and analyzed by ANOVA.
  
  
  RESULTS
  There were no significant differences in the RA groups. Exposure to hyperoxia resulted in a decrease in vascular density and RAC, with a significant increase in MLI, RVSP, and the percentage of partially and fully muscularized pulmonary arterioles. Administration of both male and female MSC significantly improved vascular density, alveolarization, RVSP, percent of muscularized vessels and alveolarization. Interestingly, the improvement in PH and vascular remodeling was more robust in the hyperoxic rodents who received MSC from female donors. In keeping with our hypothesis, male animals receiving female MSC, had a greater improvement in vascular remodeling. This was accompanied by a more significant decrease in lung pro-inflammatory markers and a larger increase in anti-inflammatory and pro-angiogenic markers in male rodents that received female MSC. There were no significant differences in MSC engraftment among groups.
  
  
  CONCLUSIONS
  Female BM-derived MSC have greater therapeutic efficacy than male MSC in reducing neonatal hyperoxia-induced lung inflammation and vascular remodeling. Furthermore, the beneficial effects of female MSC were more pronounced in male animals. Together, these findings suggest that female MSC maybe the most potent BM-derived MSC population for lung repair in severe BPD complicated by PH.
authors.affiliation: Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States of America.|Batchelor Children's Research Institute, University of Miami Miller School of Medicine, Miami, FL, United States of America.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Sammour
authors.affiliation: Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States of America.|Batchelor Children's Research Institute, University of Miami Miller School of Medicine, Miami, FL, United States of America.
authors.forename: Santhosh
authors.initials: S
authors.lastname: Somashekar
authors.affiliation: Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States of America.|Batchelor Children's Research Institute, University of Miami Miller School of Medicine, Miami, FL, United States of America.
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States of America.
authors.forename: Sunil
authors.initials: S
authors.lastname: Batlahally
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, United States of America.
authors.forename: Matthew
authors.initials: M
authors.lastname: Breton
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, United States of America.
authors.forename: Krystalenia
authors.initials: K
authors.lastname: Valasaki
authors.affiliation: The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, United States of America.
authors.forename: Aisha
authors.initials: A
authors.lastname: Khan
authors.affiliation: Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States of America.|Batchelor Children's Research Institute, University of Miami Miller School of Medicine, Miami, FL, United States of America.
authors.forename: Shu
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States of America.|Batchelor Children's Research Institute, University of Miami Miller School of Medicine, Miami, FL, United States of America.|The Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, United States of America.
authors.forename: Karen C
authors.identifier: http://orcid.org/0000-0002-3921-8467
authors.initials: KC
authors.lastname: Young
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure; D001854:Bone Marrow Cells / Q000166:cytology; D001997:Bronchopulmonary Dysplasia / Q000209:etiology / Q000628:therapy*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D018496:Hyperoxia; D006976:Hypertension, Pulmonary / Q000150:complications; D016753:Interleukin-10 / Q000378:metabolism; D008168:Lung / Q000473:pathology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D018919:Neovascularization, Physiologic; D011650:Pulmonary Alveoli / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D066253:Vascular Remodeling
chemical_list: D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D016753:Interleukin-10