A112: Prevention of Late Stage Renal Failure in BXSB SLE Mouse Model with Human Bone Marrow Derived Mesenchymal Stem Cell Treatment
Authors: Hulya Bukulmez, Asuman Bilgin, Arnold I. Caplan, Olcay Jones
Journal: Arthritis & Rheumatology (2014)

Background/Purpose:

The purpose of the study is to adequately regenerate renal tissue to sustain dialysis free survival by human bone marrow derived mesenchymal stem cells (hMSC) infusion to the SLE mouse model (BXSB mice). We aimed to test whether injection of single cell suspension into aged male BXSB either via intracarotid artery or under the renal capsule would prevent late stage kidney failure.



Methods:

Mice, BXSB (n = 15) and C57Bl/6 (n = 3), were received from Jackson Laboratories, in January 2013. At 17 weeks of age we injected (n = 4) BXSB mice with 1,000,000 hMSCs via intracarotid artery. The procedure was repeated at 19 weeks of age for (n = 3) BXSB mice. At 20 weeks of age we injected (n = 2) BXSB mice and (n = 2) C57Bl/6 mice with 1,000,000 human bone marrow derived MSCs under the renal capsule of the left kidneys. Mice then were followed up for 6 or 9 weeks duration, depending on intrarenal or intracarotid, and then sacrificed. Post mortem renal pathology, and targeted gene expression in renal parenchyma for inflammation and fibrosis were determined.



Results:

H&E stained sections of renal parenchyma of 26 week old BXSB (n = 4) showed moderate focal segmental and global glomerulosclerosis, tuft adhesions to the capsule, tubular dilatation and microcysts, protein casts, and matrix deposition. Glomerular sizes were enlarged. Age and sex matched littermate BXSB mouse 9 weeks after intracarotid hMSC injection showed only minor segmental sclerosis, mild glomerular enlargement with normal tubular structure. Glomerular sizes were still much enlarged. There was no glomerular sclerosis. The other two littermates that were injected with hMSCs intrarenaly (L) kidney showed even more significant improvement as compared to intracarotid hMSC injected BXSB mice. There was no glomerulosclerosis in either kidney. Left kidney that received the MSC injections showed normal tubular and vessel walls, and glomeruli except borderline cellular increase. R kidney showed mild segmental necrosis but normal tubular structure. In both L and R kidneys minimal regenerative changes in the tubules was also observed.



RT-PCR analysis of kidneys showed remarkable suppression of IL-17, which correlates with nephritis activity in SLE models, and significant decrease in CTLA4 expression, a co-stimulatory molecule that plays role in in B and T cell interaction, in kidneys injected with hMSCs. Similarly, there was significant decrease in the mRNA expression of IL-17 and CTLA4 in the intracarotid injected BXSB mice as compared to uninjected BXSB controls.



Conclusion:

Treatment with single cell suspension of hMSCs in BXSB mice prevented/delayed renal failure both clinically and histopathologically. Pathways that are involved in Th17 activation and IL-17 secretion which correlates with SLE nephritis activity were significantly suppressed after hMSC treatment in BXSB mice. In addition co-stimulatory molecule activity CTLA4 that play roles in B cells activation of T cells was diminished after hMSC treatment.



We suggest that MSCs are efficient treatments in delaying or preventing end stage kidney disease in BXSB animal model of SLE. In human MSCs might also be therapeutic in lupus end stage kidney disease.