title: Human Chorionic Stem Cells: Podocyte Differentiation and Potential for the Treatment of Alport Syndrome.
abstract: Alport syndrome (AS) is a hereditary glomerulopathy caused by a mutation in type IV collagen genes, which disrupts glomerular basement membrane, leading to progressive glomerulosclerosis and end-stage renal failure. There is at present no cure for AS, and cell-based therapies offer promise to improve renal function. In this study, we found that human first trimester fetal chorionic stem cells (CSC) are able to migrate to glomeruli and differentiate down the podocyte lineage in vitro and in vivo. When transplanted into 7-week-old Alport 129Sv-Col4α3(tm1Dec)/J (-/-) mice, a single intraperitoneal injection of CSC significantly lowered blood urea and urine proteinuria levels over the ensuing 2 weeks. In addition, nearly two-thirds of transplanted -/- mice maintained their weight above the 80% welfare threshold, with both males and females weighing more than age-matched nontransplanted -/- mice. This was associated with less renal cortical fibrosis and interstitial inflammation compared to nontransplanted mice as shown by reduction in murine CD4, CD68, and CD45.2 cells. Transplanted CSC homed to glomeruli, where they expressed CR1, VEGFA, SYNAPTOPODIN, CD2AP, and PODOCIN at the RNA level and produced PODOCIN, CD2AP, and COLIVα3 proteins in nontransplanted -/- mice, indicating that CSC have adopted a podocyte phenotype. Together, these data indicate that CSC may be used to delay progression of renal pathology by a combination of anti-inflammatory effects and replacement of the defective resident podocytes.
authors.affiliation: 1 Department of Maternal and Fetal Medicine, Institute for Women's Health, University College London , London, United Kingdom .
authors.forename: Dafni
authors.initials: D
authors.lastname: Moschidou
authors.affiliation: 1 Department of Maternal and Fetal Medicine, Institute for Women's Health, University College London , London, United Kingdom .
authors.forename: Michelangelo
authors.initials: M
authors.lastname: Corcelli
authors.affiliation: 1 Department of Maternal and Fetal Medicine, Institute for Women's Health, University College London , London, United Kingdom .
authors.forename: Kwan-Leong
authors.initials: KL
authors.lastname: Hau
authors.affiliation: 1 Department of Maternal and Fetal Medicine, Institute for Women's Health, University College London , London, United Kingdom .
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Ekwalla
authors.affiliation: 2 Division of Immunity and Inflammation, Faculty of Medicine, Imperial College London , London, United Kingdom .
authors.forename: Jacques V
authors.initials: JV
authors.lastname: Behmoaras
authors.affiliation: 3 Department of Stem Cells and Regenerative Medicine, Institute of Child Health, University College London , London, United Kingdom .
authors.forename: Paolo
authors.initials: P
authors.lastname: De Coppi
authors.affiliation: 1 Department of Maternal and Fetal Medicine, Institute for Women's Health, University College London , London, United Kingdom .
authors.forename: Anna L
authors.initials: AL
authors.lastname: David
authors.affiliation: 4 Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool , Liverpool, United Kingdom .
authors.forename: George
authors.initials: G
authors.lastname: Bou-Gharios
authors.affiliation: 2 Division of Immunity and Inflammation, Faculty of Medicine, Imperial College London , London, United Kingdom .
authors.forename: H Terence
authors.initials: HT
authors.lastname: Cook
authors.affiliation: 2 Division of Immunity and Inflammation, Faculty of Medicine, Imperial College London , London, United Kingdom .
authors.forename: Charles D
authors.initials: CD
authors.lastname: Pusey
authors.affiliation: 5 UQ Centre for Clinical Research, University of Queensland , Brisbane, Queensland, Australia .
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Fisk
authors.affiliation: 1 Department of Maternal and Fetal Medicine, Institute for Women's Health, University College London , London, United Kingdom .
authors.forename: Pascale V
authors.initials: PV
authors.lastname: Guillot
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D002823:Chorion / Q000166:cytology* / Q000637:transplantation; D018920:Coculture Techniques; D024141:Collagen Type IV / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005355:Fibrosis; D006801:Humans; D007249:Inflammation / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007672:Kidney Cortex / Q000473:pathology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D009394:Nephritis, Hereditary / Q000473:pathology / Q000628:therapy*; D010641:Phenotype; D050199:Podocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism
chemical_list: D015415:Biomarkers; D024141:Collagen Type IV; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D012333:RNA, Messenger