title: Direct reprogramming of human bone marrow stromal cells into functional renal cells using cell-free extracts.
abstract: The application of cell-based therapies in regenerative medicine is gaining recognition. Here, we show that human bone marrow stromal cells (BMSCs), also known as bone-marrow-derived mesenchymal cells, can be reprogrammed into renal proximal tubular-like epithelial cells using cell-free extracts. Streptolysin-O-permeabilized BMSCs exposed to HK2-cell extracts underwent morphological changes-formation of "domes" and tubule-like structures-and acquired epithelial functional properties such as transepithelial-resistance, albumin-binding, and uptake and specific markers E-cadherin and aquaporin-1. Transmission electron microscopy revealed the presence of brush border microvilli and tight intercellular contacts. RNA sequencing showed tubular epithelial transcript abundance and revealed the upregulation of components of the EGFR pathway. Reprogrammed BMSCs integrated into self-forming kidney tissue and formed tubular structures. Reprogrammed BMSCs infused in immunodeficient mice with cisplatin-induced acute kidney injury engrafted into proximal tubuli, reduced renal injury and improved function. Thus, reprogrammed BMSCs are a promising cell resource for future cell therapy.
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, 24126 Bergamo, Italy. Electronic address: evangelia.papadimou@marionegri.it.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Papadimou
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, 24126 Bergamo, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Morigi
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," 24020 Ranica, Italy.
authors.forename: Paraskevas
authors.initials: P
authors.lastname: Iatropoulos
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, 24126 Bergamo, Italy.
authors.forename: Christodoulos
authors.initials: C
authors.lastname: Xinaris
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, 24126 Bergamo, Italy.
authors.forename: Susanna
authors.initials: S
authors.lastname: Tomasoni
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, 24126 Bergamo, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Benedetti
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, 24126 Bergamo, Italy.
authors.forename: Lorena
authors.initials: L
authors.lastname: Longaretti
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, 24126 Bergamo, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Rota
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," 24020 Ranica, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Todeschini
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, 24126 Bergamo, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Rizzo
authors.affiliation: Laboratory of Cellular Therapy "G. Lanzani," USC Hematology, 24122 Bergamo, Italy.
authors.forename: Martino
authors.initials: M
authors.lastname: Introna
authors.affiliation: Department of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri," 20156 Milan, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Grazia de Simoni
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, 24126 Bergamo, Italy; IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Clinical Research Center for Rare Diseases "Aldo e Cele Daccò," 24020 Ranica, Italy; Unit of Nephrology and Dialysis, Azienda Ospedaliera Papa Giovanni XXIII, 24127 Bergamo, Italy. Electronic address: giuseppe.remuzzi@marionegri.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
authors.affiliation: Department of Medicine, Renal Research Institute, New York Medical College, 15 Dana Road, BSB C-06, Valhalla, NY 10595, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Goligorsky
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, 24126 Bergamo, Italy.
authors.forename: Ariela
authors.initials: A
authors.lastname: Benigni
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002461:Cell Line, Transformed; D002474:Cell-Free System; D065150:Cellular Reprogramming; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000166:cytology*; D007687:Kidney Tubules, Proximal / Q000166:cytology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D059467:Transcriptome