title: Clinical-Grade Isolated Human Kidney Perivascular Stromal Cells as an Organotypic Cell Source for Kidney Regenerative Medicine.
abstract: Mesenchymal stromal cells (MSCs) are immunomodulatory and tissue homeostatic cells that have shown beneficial effects in kidney diseases and transplantation. Perivascular stromal cells (PSCs) identified within several different organs share characteristics of bone marrow-derived MSCs (BM-MSCs). These PSCs may also possess tissue-specific properties and play a role in local tissue homeostasis. We hypothesized that human kidney-derived PSCs (hkPSCs) would elicit improved kidney repair in comparison with BM-MSCs. Here we introduce a novel, clinical-grade isolation method of hkPSCs from cadaveric kidneys by enriching for the perivascular marker, NG2. hkPSCs show strong transcriptional similarities to BM-MSCs but also show organotypic expression signatures, including the HoxD10 and HoxD11 nephrogenic transcription factors. Comparable to BM-MSCs, hkPSCs showed immunosuppressive potential and, when cocultured with endothelial cells, vascular plexus formation was supported, which was specifically in the hkPSCs accompanied by an increased NG2 expression. hkPSCs did not undergo myofibroblast transformation after exposure to transforming growth factor-β, further corroborating their potential regulatory role in tissue homeostasis. This was further supported by the observation that hkPSCs induced accelerated repair in a tubular epithelial wound scratch assay, which was mediated through hepatocyte growth factor release. In vivo, in a neonatal kidney injection model, hkPSCs reintegrated and survived in the interstitial compartment, whereas BM-MSCs did not show this potential. Moreover, hkPSCs gave protection against the development of acute kidney injury in vivo in a model of rhabdomyolysis-mediated nephrotoxicity. Overall, this suggests a superior therapeutic potential for the use of hkPSCs and their secretome in the treatment of kidney diseases. Stem Cells Translational Medicine 2017;6:405-418.
authors.affiliation: Department of Nephrology, Leiden University Medical Centre, Leiden, The Netherlands.|Einthoven Laboratory of Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Daniëlle G
authors.initials: DG
authors.lastname: Leuning
authors.affiliation: Department of Nephrology, Leiden University Medical Centre, Leiden, The Netherlands.|Einthoven Laboratory of Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Marlies E J
authors.initials: ME
authors.lastname: Reinders
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Joan
authors.initials: J
authors.lastname: Li
authors.affiliation: Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies, University of Florence, Florence, Italy.|Department of Biomedical, Experimental, and Clinical Sciences, University of Florence, Florence, Italy.
authors.forename: Anna J
authors.initials: AJ
authors.lastname: Peired
authors.affiliation: Department of Nephrology, Leiden University Medical Centre, Leiden, The Netherlands.|Einthoven Laboratory of Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: Lievers
authors.affiliation: Department of Nephrology, Leiden University Medical Centre, Leiden, The Netherlands.|Einthoven Laboratory of Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Hetty C
authors.initials: HC
authors.lastname: de Boer
authors.affiliation: Department of Immunology and Hematology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Willem E
authors.initials: WE
authors.lastname: Fibbe
authors.affiliation: Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies, University of Florence, Florence, Italy.|Department of Biomedical, Experimental, and Clinical Sciences, University of Florence, Florence, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Romagnani
authors.affiliation: Department of Nephrology, Leiden University Medical Centre, Leiden, The Netherlands.|Einthoven Laboratory of Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands.|Department of Immunology and Hematology, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Cees
authors.initials: C
authors.lastname: van Kooten
authors.affiliation: Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.|Murdoch Childrens Research Institute, Parkville, Melbourne, Victoria, Australia.|Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Melissa H
authors.initials: MH
authors.lastname: Little
authors.affiliation: Department of Nephrology, Leiden University Medical Centre, Leiden, The Netherlands.|Einthoven Laboratory of Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Marten A
authors.initials: MA
authors.lastname: Engelse
authors.affiliation: Department of Nephrology, Leiden University Medical Centre, Leiden, The Netherlands.|Einthoven Laboratory of Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Ton J
authors.initials: TJ
authors.lastname: Rabelink
mesh_terms: D000818:Animals; D000941:Antigens / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D002465:Cell Movement; D049109:Cell Proliferation; D002469:Cell Separation / Q000379:methods*; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005838:Genotype; D018398:Homeodomain Proteins / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000473:pathology / Q000502:physiology; D006801:Humans; D007668:Kidney / Q000098:blood supply* / Q000166:cytology*; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D016030:Kidney Transplantation / Q000379:methods*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000502:physiology*; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D010641:Phenotype; D011509:Proteoglycans / Q000378:metabolism; D012038:Regeneration; D044968:Regenerative Medicine / Q000379:methods*; D014157:Transcription Factors / Q000378:metabolism; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D000941:Antigens; D015415:Biomarkers; D018398:Homeodomain Proteins; D011509:Proteoglycans; D014157:Transcription Factors; D000099216:Chondroitin Sulfate Proteoglycan 4; C489493:HOXD11 protein, human; C072064:HOXD10 protein, human
keywords: Cellular therapy; Clinical translation; Kidney; Mesenchymal stromal cells; Pericytes; Stromal cells; Tissue regeneration; Tissue-specific stem cells