Adipose tissue-derived stem cell treatment prevents renal disease progression.
Adipose tissue-derived stem cells (ASCs) are an attractive source of stem cells with regenerative properties that are similar to those of bone marrow stem cells. Here, we analyze the role of ASCs in reducing the progression of kidney fibrosis. Progressive renal fibrosis was achieved  by unilateral clamping of the renal pedicle in mice for 1 h; after that, the kidney was reperfused immediately. Four hours after the surgery, 2 × 10(5) ASCs were intraperitoneally administered, and mice were followed for 24 h posttreatment and then at some other time interval  for the next 6 weeks. Also, animals were treated with 2 × 10(5) ASCs at 6 weeks after reperfusion and sacrificed 4 weeks later to study their effect when interstitial fibrosis is already present. At 24 h after reperfusion, ASC-treated animals showed reduced renal dysfunction  and enhanced regenerative tubular processes. Renal mRNA expression of IL-6 and TNF was decreased in ASC-treated animals, whereas IL-4, IL-10, and HO-1 expression increased despite a lack of ASCs in the kidneys as determined by SRY analysis. As expected, untreated kidneys shrank at 6 weeks,  whereas the kidneys of ASC-treated animals remained normal in size, showed less collagen deposition, and decreased staining for FSP-1, type I collagen, and Hypoxyprobe. The renal protection seen in ASC-treated animals was followed by reduced serum levels of TNF-α, KC, RANTES, and IL-1α.  Surprisingly, treatment with ASCs at 6 weeks, when animals already showed installed fibrosis, demonstrated amelioration of functional parameters, with less tissue fibrosis observed and reduced mRNA expression of type I collagen and vimentin. ASC therapy can improve functional parameters and  reduce progression of renal fibrosis at early and later times after injury, mostly due to early modulation of the inflammatory response and to less hypoxia, thereby reducing the epithelial-mesenchymal transition.
Experimental and Clinical Immunology Laboratory, Division of Nephrology, Federal University of São Paulo, Escola Paulista de Medicina, São Paulo, Brazil.
Cassiano
C
Donizetti-Oliveira
Patricia
P
Semedo
Marina
M
Burgos-Silva
Marco Antonio
MA
Cenedeze
Denise Maria Avancini Costa
DM
Malheiros
Marlene A
MA
Reis
Alvaro
A
Pacheco-Silva
Niels Olsen Saraiva
NO
Câmara
D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D018946:Chemokine CCL5 / Q000097:blood; D018925:Chemokines / Q000097:blood; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D053582:Interleukin-1alpha / Q000097:blood; D015847:Interleukin-4 / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007511:Ischemia / Q000150:complications / Q000473:pathology / Q000628:therapy; D007674:Kidney Diseases / Q000150:complications / Q000473:pathology* / Q000628:therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000378:metabolism; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014746:Vimentin / Q000235:genetics / Q000378:metabolism
D018946:Chemokine CCL5; D018925:Chemokines; D024042:Collagen Type I; D053582:Interleukin-1alpha; D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D014746:Vimentin; D016753:Interleukin-10; C074302:keratinocyte-derived chemokines; D015847:Interleukin-4; D051547:Heme Oxygenase-1