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Steens, J.* ; Unger, K. ; Klar, L.* ; Neureiter, A.* ; Wieber, K.* ; Hess J. ; Jakob, H.G.* ; Klump, H.* ; Klein, D.*

Direct conversion of human fibroblasts into therapeutically active vascular wall-typical mesenchymal stem cells.

Cell. Mol. Life Sci. 77, 3401–3422 (2020)
Postprint DOI PMC
Open Access Green
Cell-based therapies using adult stem cells are promising options for the treatment of a number of diseases including autoimmune and cardiovascular disorders. Among these, vascular wall-derived mesenchymal stem cells (VW-MSCs) might be particularly well suited for the protection and curative treatment of vascular damage because of their tissue-specific action. Here we report a novel method for the direct conversion of human skin fibroblasts towards MSCs using a VW-MSC-specific gene code (HOXB7, HOXC6 and HOXC8) that directs cell fate conversion bypassing pluripotency. This direct programming approach using either a self-inactivating (SIN) lentiviral vector expressing the VW-MSC-specific HOX-code or a tetracycline-controlled Tet-On system for doxycycline-inducible gene expressions of HOXB7, HOXC6 and HOXC8 successfully mediated the generation of VW-typical MSCs with classical MSC characteristics in vitro and in vivo. The induced VW-MSCs (iVW-MSCs) fulfilled all criteria of MSCs as defined by the International Society for Cellular Therapy (ISCT). In terms of multipotency and clonogenicity, which are important specific properties to discriminate MSCs from fibroblasts, iVW-MSCs behaved like primary ex vivo isolated VW-MSCs and shared similar molecular and DNA methylation signatures. With respect to their therapeutic potential, these cells suppressed lymphocyte proliferation in vitro, and protected mice against vascular damage in a mouse model of radiation-induced pneumopathy in vivo, as well as ex vivo cultured human lung tissue. The feasibility to obtain patient-specific VW-MSCs from fibroblasts in large amounts by a direct conversion into induced VW-MSCs could potentially open avenues towards novel, MSC-based therapies.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Adult Stem Cells ; Fibroblast ; Hox Code ; Lineage Conversion ; Radioprotection ; Stem Cell Therapy ; Vascular Wall
ISSN (print) / ISBN 1420-682X
e-ISSN 1420-9071
Zeitschrift Cellular and Molecular Life Sciences - CMLS
Quellenangaben Band: 77, Heft: , Seiten: 3401–3422 Artikelnummer: , Supplement: ,
Verlag Birkhäuser
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Translational Metabolic Oncology (TMO)
CCG Personalized Radiotherapy in Head and Neck Cancer (KKG-KRT)