title: Effect of 17β-estradiol on mediators involved in mesenchymal stromal cell trafficking in cell therapy of diabetes.
abstract: OBJECTIVE
  Mesenchymal stromal cells (MSCs) have shown great promise for cell therapy of a wide range of diseases such as diabetes. However, insufficient viability of transplanted cells reaching to damaged tissues has limited their potential therapeutic effects. Expression of estrogen receptors on stem cells may suggest a role for 17β-estradiol (E2) in regulating some functions in these cells. There is evidence that E2 enhances homing of stem cells. Induction of hypoxia-inducible factor-1α (HIF-1α) by E2 and the profound effect of HIF-1α on migration of cells have previously been demonstrated. We investigated the effect of E2 on major mediators involved in trafficking and subsequent homing of MSCs both in vitro and in vivo in diabetic rats.
  
  
  METHODS
  E2 has been selected to improve the poor migration capacity of MSCs toward sites of injury. MSCs were incubated with different concentrations of E2 for varying periods of time to investigate whether estradiol treatment could be effective to enhance the efficiency of MSC transplantation.
  
  
  RESULTS
  E2 significantly enhanced the viability of the cells that were blocked by ICI 182,780 (estrogen receptor antagonist). E2 also increased HIF-1α, CXC chemokine receptor 4 and C-C chemokine receptor 2 protein and messenger RNA levels measured by Western blot and reverse transcription-polymerase chain reaction. The enzymatic activity of matrix metalloproteinase 2 and metalloproteinase 9 was elevated in E2-treated cells through the use of gelatin zymography. Finally, the improved migration capacity of E2-treated MSCs was evaluated with the use of a Boyden chamber and in vivo migration assays.
  
  
  CONCLUSIONS
  Our data support that conditioning of MSCs with E2 promotes migration of cells in cultured MSCs in vitro and in a diabetic rat model in vivo through regulation of major mediators of cell trafficking.
authors.affiliation: Razi Drug Research Center and Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
authors.forename: Solmaz
authors.initials: S
authors.lastname: Mirzamohammadi
authors.affiliation: Razi Drug Research Center and Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
authors.forename: Ehsan
authors.initials: E
authors.lastname: Aali
authors.affiliation: Department of Molecular Medicine, Hamedan University of Medical Sciences, Hamedan, Iran.
authors.forename: Rezvan
authors.initials: R
authors.lastname: Najafi
authors.affiliation: Tissue Engineering Group (TEG) and Research, National Orthopedic Centre of Excellence in Research and Learning (NOCERAL), Department of Orthopedics, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Tunku
authors.initials: T
authors.lastname: Kamarul
authors.affiliation: Razi Drug Research Center and Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
authors.forename: Mehrnaz
authors.initials: M
authors.lastname: Mehrabani
authors.affiliation: Razi Drug Research Center and Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
authors.forename: Azadeh
authors.initials: A
authors.lastname: Aminzadeh
authors.affiliation: Razi Drug Research Center and Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Department of Tissue Engineering and Cell Therapy, School of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran. Electronic address: sharifal@Yahoo.com.
authors.forename: Ali Mohammad
authors.initials: AM
authors.lastname: Sharifi
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D064987:Cell- and Tissue-Based Therapy / Q000379:methods; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000628:therapy*; D004958:Estradiol / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000187:drug effects; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects*; D017208:Rats, Wistar; D019718:Receptors, CXCR4 / Q000187:drug effects
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019718:Receptors, CXCR4; D004958:Estradiol
keywords: 17β-estradiol; CCR2; CXCR4; HIF-1α; mesenchymal stromal cell migration