title: Mesenchymal stem cells increase T-regulatory cells and improve healing following trauma and hemorrhagic shock.
abstract: BACKGROUND
  Rodent lungs undergo full histologic recovery within 1 week following unilateral lung contusion (LC). However, when LC is followed by hemorrhagic shock (HS), healing is impaired. We hypothesize that the intravenous administration of mesenchymal stem cells (MSCs) in animals undergoing combined LC followed by HS (LCHS) will improve wound healing.
  
  
  METHODS
  Male Sprague-Dawley rats (n = 5-6 per group) were subjected to LCHS with or without the injection of a single intravenous dose of 5 × 10 MSCs following return of shed blood after HS. Rats were sacrificed 7 days following injury. Flow cytometry was used to determine the T-regulatory cell (Treg) population in peripheral blood. Lung histology was graded using a well-established lung injury score (LIS). Components of the LIS include average inflammatory cells per high-power field over 30 fields, interstitial edema, pulmonary edema, and alveolar integrity, with total scores ranging from 0 to 11. Data were analyzed by analysis of variance followed by Tukey's multiple comparison test, expressed as mean (SD). p < 0.05 was considered significant.
  
  
  RESULTS
  Seven days following isolated LC, animals demonstrated lung healing with an LIS unchanged from naive. The addition of HS resulted in a persistently elevated LIS score, whereas the addition of MSCs to LCHS decreased the LIS score back to naive levels. The change in LIS was driven by a significant decrease in edema scores. In rats undergoing LC alone, 10.5% (3.3%) of CD4 cells were Tregs. The addition of HS caused no significant change in Treg population (9.3% [0.7%]), whereas LCHS + MSC significantly increased the population to 18.2% (6.8%) in peripheral blood (p < 0.05 vs. LCHS).
  
  
  CONCLUSIONS
  Impaired wound healing following trauma and HS is improved by a single dose of MSCs given immediately after injury. This enhanced healing is associated with an increase in the Treg population and a significant decrease in lung edema score as compared with animals undergoing LCHS. Further study into the role of Tregs in MSC-mediated wound healing is warranted.
authors.affiliation: From the Division of Trauma, Department of Surgery, Rutgers New Jersey Medical School, Newark, New Jersey.
authors.forename: Amy V
authors.initials: AV
authors.lastname: Gore
authors.forename: Letitia E
authors.initials: LE
authors.lastname: Bible
authors.forename: Kimberly
authors.initials: K
authors.lastname: Song
authors.forename: David H
authors.initials: DH
authors.lastname: Livingston
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Mohr
authors.forename: Ziad C
authors.initials: ZC
authors.lastname: Sifri
mesh_terms: D000818:Animals; D003288:Contusions / Q000503:physiopathology*; D045604:Extracellular Fluid / Q000502:physiology; D005434:Flow Cytometry; D007150:Immunohistochemistry; D055370:Lung Injury / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D011654:Pulmonary Edema / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000503:physiopathology / Q000628:therapy*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D014945:Wound Healing / Q000502:physiology*