Abstract
In this study we evaluated whether administration of stem cells of neural origin (neural precursor cells, NPCs) could be protective against renal ischemia-reperfusion injury (IRI). We hypothesized that stem cell outcomes are not tissue-specific and that NPCs can improve tissue damage through paracrine mechanisms, especially due to immunomodulation. To this end, Wistar rats (200–250 g) were submitted to 1-hour ischemia and treated with NPCs (4 × 106 cells/animal) at 4 h of reperfusion. To serve as controls, ischemic animals were treated with cerebellum homogenate harvested from adult rat brain. All groups were sacrificed at 24 h of reperfusion. NPCs were isolated from rat fetus telencephalon and cultured until neurosphere formation (7 days). Before administration, NPCs were labeled with carboxyfluorescein diacetate succinimydylester (CFSE). Kidneys were harvested for analysis of cytokine profile and macrophage infiltration. At 24 h, NPC treatment resulted in a significant reduction in serum creatinine (IRI + NPC 1.21 + 0.18 vs. IRI 3.33 + 0.14 and IRI + cerebellum 2.95 + 0.78mg/dl, p < 0.05) and acute tubular necrosis (IRI + NPC 46.0 + 2.4% vs. IRI 79.7 + 14.2%, p < 0.05). NPC-CFSE and glial fibrillary acidic protein (GFAP)-positive cells (astrocyte marker) were found exclusively in renal parenchyma, which also presented GFAP and SOX-2 (an embryonic neural stem cell marker) mRNA expression. NPC treatment resulted in lower renal proinflammatory IL1-β and TNF-α expression and higher anti-inflammatory IL-4 and IL-10 transcription. NPC-treated animals also had less macrophage infiltration and decreased serum proinflammatory cytokines (IL-1β, TNF-α and INF-γ). Our data suggested that NPC therapy improved renal function by influencing immunological responses.
Journal Section:
Original Paper
References
1.
Lieberthal W, Nigam SK: Acute renal failure. II. Experimental models of acute renal failure: imperfect but indispensable. Am J Physiol Renal Physiol 2000;278:F1–F12.
[PubMed]
2.
Prockop DJ, Gregory CA, Spees JL: One strategy for cell and gene therapy: harnessing the power of adult stem cells to repair tissues. Proc Natl Acad Sci USA 2003;100(suppl 1):11917–11923.
[PubMed]
3.
Terada N, Hamazaki T, Oka M, Hoki M, Mastalerz DM, Nakano Y, Meyer EM, Morel L, Petersen BE, Scott EW: Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 2002;416:542–545.
[PubMed]
4.
Spees JL, Olson SD, Ylostalo J, Lynch PJ, Smith J, Perry A, Peister A, Wang MY, Prockop DJ: Differentiation, cell fusion, and nuclear fusion during ex vivo repair of epithelium by human adult stem cells from bone marrow stroma. Proc Natl Acad Sci USA 2003;100:2397–2402.
[PubMed]
5.
Togel F, Hu Z, Weiss K, Isaac J, Lange C, Westenfelder C: Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol 2005;289:F31–F42.
[PubMed]
6.
Azizi SA, Stokes D, Augelli BJ, DiGirolamo C, Prockop DJ: Engraftment and migration of human bone marrow stromal cells implanted in the brains of albino rats – similarities to astrocyte grafts. Proc Natl Acad Sci USA 1998;95:3908–3913.
[PubMed]
7.
Orth SR, Ritz E, Suter-Crazzolara C: Glial cell line-derived neurotrophic factor (GDNF) is expressed in the human kidney and is a growth factor for human mesangial cells. Nephrol Dial Transplant 2000;15:589–595.
[PubMed]
8.
Shi H, Patschan D, Dietz GP, Bähr M, Plotkin M, Goligorsky MS: Glial cell line-derived neurotrophic growth factor increases motility and survival of cultured mesenchymal stem cells and ameliorates acute kidney injury. Am J Physiol Renal Physiol 2008;294:F229–F235.
[PubMed]
9.
Gage FH, Ray J, Fisher LJ: Isolation, characterization, and use of stem cells from the CNS. Annu Rev Neurosci 1995;18:159–192.
[PubMed]
10.
Svendsen CN, Caldwell MA, Ostenfeld T: Human neural stem cells: isolation, expansion and transplantation. Brain Pathol 1999;9:499–513.
[PubMed]
11.
Martins AH, Alves JM, Trujillo CA, Schwindt TT, Barnabe GF, Motta FL, Guimaraes AO, Casarini DE, Mello LE, Pesquero JB, Ulrich H: Kinin-B2 receptor expression and activity during differentiation of embryonic rat neurospheres. Cytometry A 2008;73:361–368.
[PubMed]
12.
Reynolds BA, Tetzlaff W, Weiss S: A multipotent EGF-responsive striatal embryonic progenitor cell produces neurons and astrocytes. J Neurosci 1992;12:4565–4574.
[PubMed]
13.
Reynolds BA, Weiss S: Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 1992;255:1707–1710.
[PubMed]
14.
Reynolds BA, Weiss S: Clonal and population analyses demonstrate that an EGF-responsive mammalian embryonic CNS precursor is a stem cell. Dev Biol 1996;175:1–13.
[PubMed]
15.
Einstein O, Ben-Menachem-Tzidon O, Mizrachi-Kol R, Reinhartz E, Grigoriadis N, Ben-Hur T: Survival of neural precursor cells in growth factor-poor environment: implications for transplantation in chronic disease. Glia 2006;53:449–455.
[PubMed]
16.
Ben-Hur T: Immunomodulation by neural stem cells. J Neurol Sci 2008;265:102–104.
[PubMed]
17.
Pluchino S, Zanotti L, Rossi B, Brambilla E, Ottoboni L, Salani G, Martinello M, Cattalini A, Bergami A, Furlan R, Comi G, Constantin G, Martino G: Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature 2005;436:266–271.
[PubMed]
18.
Sheng WS, Hu S, Ni HT, Rowen TN, Lokensgard JR, Peterson PK: TNF-alpha-induced chemokine production and apoptosis in human neural precursor cells. J Leukoc Biol 2005;78:1233–1241.
[PubMed]
19.
Zheng XS, Yang XF, Liu WG, Pan DS, Hu WW, Li G: Transplantation of neural stem cells into the traumatized brain induces lymphocyte infiltration. Brain Inj 2007;21:275–278.
[PubMed]
20.
Louis SA, Reynolds BA: Generation and differentiation of neurospheres from murine embryonic day 14 central nervous system tissue. Methods Mol Biol 2005;290:265–280.
[PubMed]
21.
Feitoza CQ, Sanders H, Cenedeze M, Camara NO, Pacheco-Silva A: Pretreatment with indomethacin protects from acute renal failure following ischemia-reperfusion injury. Transplant Proc 2002;34:2979–2980.
[PubMed]
22.
Grimaldi P, Rossi F: Lack of neurogenesis in the adult rat cerebellum after Purkinje cell degeneration and growth factor infusion. Eur J Neurosci 2006;23:2657–2668.
[PubMed]
23.
Ponti G, Peretto P, Bonfanti L: A subpial, transitory germinal zone forms chains of neuronal precursors in the rabbit cerebellum. Dev Biol 2006;294:168–180.
[PubMed]
24.
Klein C, Butt SJ, Machold RP, Johnson JE, Fishell G: Cerebellum- and forebrain- derived stem cells possess intrinsic regional character. Development 2005;132:4497–4508.
[PubMed]
25.
Capone C, Frigerio S, Fumagalli S, Gelati M, Principato MC, Storini C, Montinaro M, Kraftsik R, Curtis MD, Parati E, Simoni MG: Neurosphere-derived cells exert a neuroprotective action by changing the ischemic microenvironment. PLoS ONE 2007;2:e373.
[PubMed]
26.
Chute JP: Stem cell homing. Curr Opin Hematol 2006;13:399–406.
[PubMed]
27.
Krampera M, Glennie S, Dyson J, Scott D, Laylor R, Simpson E, Dazzi F: Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 2003;101:3722–3729.
[PubMed]
28.
Djouad F, Plence P, Bony C, Tropel P, Apparailly F, Sany J, Noel D, Jorgensen C: Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood 2003;102:3837–3844.
[PubMed]
29.
Spaggiari GM, Capobianco A, Becchetti S, Mingari MC, Moretta L: Mesenchymal stem cell-natural killer cell interactions: evidence that activated NK cells are capable of killing MSCS, whereas MSCS can inhibit IL-2-induced NK-cell proliferation. Blood 2006;107:1484–1490.
[PubMed]
30.
Stagg J, Pommey S, Eliopoulos N, Galipeau J: Interferon-gamma-stimulated marrow stromal cells: a new type of nonhematopoietic antigen-presenting cell. Blood 2006;107:2570–2577.
[PubMed]
31.
Burne MJ, Daniels F, El Ghandour A, Mauiyyedi S, Colvin RB, O’Donnell MP, Rabb H: Identification of the CD4(+) T cell as a major pathogenic factor in ischemic acute renal failure. J Clin Invest 2001;108:1283–1290.
[PubMed]
32.
Yokota N, Burne-Taney M, Racusen L, Rabb H: Contrasting roles for STAT4 and STAT6 signal transduction pathways in murine renal ischemia-reperfusion injury. Am J Physiol Renal Physiol 2003;285:F319–F325.
[PubMed]
33.
Shen XD, Ke B, Zhai Y, Gao F, Anselmo D, Lassman CR, Busuttil RW, Kupiec-Weglinski JW: Stat4 and Stat6 signaling in hepatic ischemia/reperfusion injury in mice: HO-1 dependence of Stat4 disruption-mediated cytoprotection. Hepatology 2003;37:296–303.
[PubMed]
34.
Rabb H, Daniels F, O’Donnell M, Haq M, Saba SR, Keane W, Tang WW: Pathophysiological role of T lymphocytes in renal ischemia-reperfusion injury in mice. Am J Physiol Renal Physiol 2000;279:F525–F531.
[PubMed]
35.
Ji JF, He BP, Dheen ST, Tay SS: Interactions of chemokines and chemokine receptors mediate the migration of mesenchymal stem cells to the impaired site in the brain after hypoglossal nerve injury. Stem Cells 2004;22:415–427.
[PubMed]
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