title: Mesenchymal stem cell therapy ameliorates diabetic nephropathy via the paracrine effect of renal trophic factors including exosomes.
abstract: Bone marrow-derived mesenchymal stem cells (MSCs) have contributed to the improvement of diabetic nephropathy (DN); however, the actual mediator of this effect and its role has not been characterized thoroughly. We investigated the effects of MSC therapy on DN, focusing on the paracrine effect of renal trophic factors, including exosomes secreted by MSCs. MSCs and MSC-conditioned medium (MSC-CM) as renal trophic factors were administered in parallel to high-fat diet (HFD)-induced type 2 diabetic mice and streptozotocin (STZ)-induced insulin-deficient diabetic mice. Both therapies showed approximately equivalent curative effects, as each inhibited the exacerbation of albuminuria. They also suppressed the excessive infiltration of BMDCs into the kidney by regulating the expression of the adhesion molecule ICAM-1. Proinflammatory cytokine expression (e.g., TNF-α) and fibrosis in tubular interstitium were inhibited. TGF-β1 expression was down-regulated and tight junction protein expression (e.g., ZO-1) was maintained, which sequentially suppressed the epithelial-to-mesenchymal transition of tubular epithelial cells (TECs). Exosomes purified from MSC-CM exerted an anti-apoptotic effect and protected tight junction structure in TECs. The increase of glomerular mesangium substrate was inhibited in HFD-diabetic mice. MSC therapy is a promising tool to prevent DN via the paracrine effect of renal trophic factors including exosomes due to its multifactorial action.
authors.affiliation: Second Department of Anatomy, Sapporo Medical University, Japan.|Department of Diabetic Cellular Therapeutics, Sapporo Medical University, Japan.
authors.forename: Kanna
authors.initials: K
authors.lastname: Nagaishi
authors.affiliation: Second Department of Anatomy, Sapporo Medical University, Japan.|Department of Diabetic Cellular Therapeutics, Sapporo Medical University, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Mizue
authors.affiliation: Second Department of Anatomy, Sapporo Medical University, Japan.|Department of Diabetic Cellular Therapeutics, Sapporo Medical University, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Chikenji
authors.affiliation: Department of Diabetic Cellular Therapeutics, Sapporo Medical University, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Otani
authors.affiliation: Second Department of Anatomy, Sapporo Medical University, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Nakano
authors.affiliation: Second Department of Anatomy, Sapporo Medical University, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Konari
authors.affiliation: Second Department of Anatomy, Sapporo Medical University, Japan.|Department of Diabetic Cellular Therapeutics, Sapporo Medical University, Japan.
authors.forename: Mineko
authors.initials: M
authors.lastname: Fujimiya
mesh_terms: D000419:Albuminuria; D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000209:etiology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D059305:Diet, High-Fat / Q000009:adverse effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D055354:Exosomes / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011917:Rats, Inbred Lew
chemical_list: D017077:Culture Media, Conditioned; D016207:Cytokines