title: Injectable hydrogel delivery plus preconditioning of mesenchymal stem cells: exploitation of SDF-1/CXCR4 axis toward enhancing the efficacy of stem cells' homing.
abstract: Clinical applications of mesenchymal stem cells (MSCs) rely on their capacity to home and engraft in the appropriate target injury tissues for the long term. However, their homing efficiency has been observed to be very poor because of the lack or modifications of homing factors SDF-1α and CXCR4 receptors. Hence, this study was designed to investigate the homing and retention of pretreated human adipose tissue-derived MSCs (hASCs) from three different delivery routes in response to SDF-1α, released from chitosan-based injectable hydrogels. After stimulation of ASCs with a hypoxia mimicking agent, the expression level and functionality of CXCR4 were analyzed by flowcytometric analysis (FACS), transwell migration assay and qPCR. Then, the homing/retention of pretreated DiI-labeled hASCs were compared through three different in vivo delivery routes, 2 weeks after transplantation in Wistar rats. The cells were tracked histologically by fluorescent microscope and by PCR for human-specific CXCR4 gene. Results showed CXCR4 has dynamic expression pattern and pretreatment of hASCs significantly up-regulates CXCR4, leading to an increase in migration capacity toward 100 ng/mL SDF-1α in vitro and homing into the subcutaneously implanted hydrogel releasing SDF-1α in vivo. Furthermore, it seems that SDF-1α is particularly important in the retention of ASCs, in addition to its chemoattraction role. In summary, the delivery route in which the ASCs were mixed with the hydrogel rather than systemic delivery and local injection and preconditioning undertaken to increase CXCR4 expression concomitant with SDF-1α delivery by the injectable hydrogel, allowed for further homing/retention of ASCs. This might be a promising way to get better therapeutic outcomes in stem cell therapy.
authors.affiliation: Stem Cell and Regenerative Medicine Research Department, Iranian Academic Center for Education, Culture Research (ACECR), Mashhad Branch, Mashhad, Iran.|Department of Biology, Ferdowsi University of Mashhad, Mashhad, Iran.
authors.forename: Hojjat
authors.initials: H
authors.lastname: Naderi-Meshkin
authors.affiliation: Department of Biology, Ferdowsi University of Mashhad, Mashhad, Iran.|Cell and Molecular Biotechnology Research Department, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran.
authors.forename: Maryam M
authors.initials: MM
authors.lastname: Matin
authors.affiliation: Stem Cell and Regenerative Medicine Research Department, Iranian Academic Center for Education, Culture Research (ACECR), Mashhad Branch, Mashhad, Iran.|Department of Biology, Ferdowsi University of Mashhad, Mashhad, Iran.
authors.forename: Asieh
authors.initials: A
authors.lastname: Heirani-Tabasi
authors.affiliation: Stem Cell and Regenerative Medicine Research Department, Iranian Academic Center for Education, Culture Research (ACECR), Mashhad Branch, Mashhad, Iran.
authors.forename: Mahdi
authors.initials: M
authors.lastname: Mirahmadi
authors.affiliation: Stem Cell and Regenerative Medicine Research Department, Iranian Academic Center for Education, Culture Research (ACECR), Mashhad Branch, Mashhad, Iran.|Department of Biology, Ferdowsi University of Mashhad, Mashhad, Iran.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Irfan-Maqsood
authors.affiliation: Department of Physiology, College of Sciences, Shiraz Branch, Islamic Azad University, Shiraz, Iran.
authors.forename: Mohmmad Amin
authors.initials: MA
authors.lastname: Edalatmanesh
authors.affiliation: Stem Cell and Regenerative Medicine Research Department, Iranian Academic Center for Education, Culture Research (ACECR), Mashhad Branch, Mashhad, Iran.
authors.forename: Mina
authors.initials: M
authors.lastname: Shahriyari
authors.affiliation: School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran.
authors.forename: Naghmeh
authors.initials: N
authors.lastname: Ahmadiankia
authors.affiliation: Department of Surgery, Faculty of Medicine, Islamic Azad University-Mashhad Branch, Mashhad, Iran.
authors.forename: Nasser Sanjar
authors.initials: NS
authors.lastname: Moussavi
authors.affiliation: Stem Cell and Regenerative Medicine Research Department, Iranian Academic Center for Education, Culture Research (ACECR), Mashhad Branch, Mashhad, Iran.
authors.forename: Hamid Reza
authors.initials: HR
authors.lastname: Bidkhori
authors.affiliation: Stem Cell and Regenerative Medicine Research Department, Iranian Academic Center for Education, Culture Research (ACECR), Mashhad Branch, Mashhad, Iran.|Cell and Molecular Biotechnology Research Department, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran.
authors.forename: Ahmad Reza
authors.initials: AR
authors.lastname: Bahrami
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000818:Animals; D002465:Cell Movement / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D054377:Chemokine CXCL12 / Q000008:administration & dosage* / Q000378:metabolism*; D005260:Female; D006801:Humans; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000008:administration & dosage*; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction; D019172:Transplantation Conditioning / Q000379:methods*
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate
keywords: SDF-1/CXCR4; cell delivery routes; chitosan-based injectable hydrogels; drug delivery systems; in situ tissue regeneration; stem cell therapy