The Contribution of Bone Marrow-Derived Cells to the Development of Renal Interstitial Fibrosis

Li, Jinhua; Deane, James A.; Campanale, Naomi Vittoria; Bertram, John F.; Ricardo, Sharon D.

doi:10.1634/stemcells.2006-0133

Cited by 104 publications

(81 citation statements)

References 55 publications

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“…Myofibroblasts are the primary source of extracellular matrix (ECM), which is deposited in the renal interstitium during fibrogenesis. The anatomic origin of interstitial myofibroblasts responsible for excessive matrix production is still an area of controversy, and various origins have been proposed including adult kidney nephrogenic progenitors, stroma, bone marrow-derived cells, damaged epithelium, and endothelium (3,(7)(8)(9)(10)(11)(12)(13)(14)(15). Most likely, interstitial myofibroblasts in renal fibrosis originate from multiple sources but to various extents; the majority, however, appears to originate from the FOXD1 lineage, which gives rise to pericytes, Abbreviations: ATA, acetylthioacetate; DMF, dimethylformamide; ECM, extracellular matrix; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GMBS, g-maleimidobutyryloxy-succinimide ester; HRP, horseradish peroxidase; HSA, human serum albumin; IF, interstitial fibrosis; IFN-gR1, IFN-g receptor 1; JAK/STAT, Janus kinase/signal transducers and activators of transcription signaling pathway; LTA, lotus tetragonolobus; LTL, lotus tetragonolobus lectin;…”

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confidence: 99%

Selective delivery of IFN‐γ to renal interstitial myofibroblasts: a novel strategy for the treatment of renal fibrosis

et al. 2014

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Renal fibrosis leads to end-stage renal disease demanding renal replacement therapy because no adequate treatment exists. IFN-g is an antifibrotic cytokine that may attenuate renal fibrosis. Systemically administered IFN-g causes side effects that may be prevented by specific drug targeting. Interstitial myofibroblasts are the effector cells in renal fibrogenesis. Here, we tested the hypothesis that cell-specific delivery of IFN-g to plateletderived growth factor receptor b (PDGFRb)-expressing myofibroblasts attenuates fibrosis in an obstructive nephropathy [unilateral ureteral obstruction (UUO)] mouse model. PEGylated IFN-g conjugated to PDGFRbrecognizing peptide [(PPB)-polyethylene glycol (PEG)-IFN-g] was tested in vitro and in vivo for antifibrotic properties and compared with free IFN-g. PDGFRb expression was >3-fold increased (P < 0.05) in mouse fibrotic UUO kidneys and colocalized with a-smooth muscle actin-positive (SMA + ) myofibroblasts.

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confidence: 99%

Selective delivery of IFN‐γ to renal interstitial myofibroblasts: a novel strategy for the treatment of renal fibrosis

et al. 2014

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“…However, it should be noted that activated resident interstitial fibroblasts may not be the only cells participating in extracellular matrix production. There have been reports that bone marrow-derived cells (39,40), transdifferentiated tubular epithelial and endothelial cells [via epithelial-to-mesenchymal (EMT) (39,41) and endothelial-tomesenchymal (EndMT) transition (4), respectively], and periadventitial cells (42,43) could also contribute to the population of interstitial matrix-producing cells in renal fibrotic disease.…”

Section: Discussionmentioning

confidence: 99%

Renal fibrosis is attenuated by targeted disruption of K _Ca 3.1 potassium channels

Grgic

Kiss

Kaistha

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

147

137

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Proliferation of interstitial fibroblasts is a hallmark of progressive renal fibrosis commonly resulting in chronic kidney failure. The intermediate-conductance Ca 2+ -activated K + channel (K Ca 3.1) has been proposed to promote mitogenesis in several cell types and contribute to disease states characterized by excessive proliferation. Here, we hypothesized that K Ca 3.1 activity is pivotal for renal fibroblast proliferation and that deficiency or pharmacological blockade of K Ca 3.1 suppresses development of renal fibrosis. We found that mitogenic stimulation up-regulated K Ca 3.1 in murine renal fibroblasts via a MEK-dependent mechanism and that selective blockade of K Ca 3.1 functions potently inhibited fibroblast proliferation by G 0 /G 1 arrest. Renal fibrosis induced by unilateral ureteral obstruction (UUO) in mice was paralleled by a robust up-regulation of K Ca 3.1 in affected kidneys. Mice lacking K Ca 3.1 (K Ca 3.1 −/− ) showed a significant reduction in fibrotic marker expression, chronic tubulointerstitial damage, collagen deposition and αSMA + cells in kidneys after UUO, whereas functional renal parenchyma was better preserved. Pharmacological treatment with the selective K Ca 3.1 blocker TRAM-34 similarly attenuated progression of UUO-induced renal fibrosis in wild-type mice and rats. In conclusion, our data demonstrate that K Ca 3.1 is involved in renal fibroblast proliferation and fibrogenesis and suggest that K Ca 3.1 may represent a therapeutic target for the treatment of fibrotic kidney disease.

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“…While Li et al [29] showed the integration of unfractionated malederived BM cells into the proximal tubules, thick ascending limbs and distal tubules and collecting ducts of female recipients, no functional improvement was seen. They proposed that whole BM may only be useful for glomerular injury.…”

Section: Bone Marrow-derived Cellsmentioning

confidence: 96%

“…They proposed that whole BM may only be useful for glomerular injury. BM may also act as a source of α-SMA-positive interstitial myofibroblasts which have been shown to participate in the production of extracellular matrix in renal fibrosis [29,30]. Finally, a recent study looked at the effects of SCF and G-CSF in a model of chronic UUO found that increased mobilization did not influence renal damage, fibrosis or inflammatory cell influx [31].…”

Section: Bone Marrow-derived Cellsmentioning

confidence: 99%

Stem cell options for kidney disease

Hopkins

Rae

et al. 2008

The Journal of Pathology

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Chronic kidney disease (CKD) is increasing at the rate of 6-8% per annum in the US alone. At present, dialysis and transplantation remain the only treatment options. However, there is hope that stem cells and regenerative medicine may provide additional regenerative options for kidney disease. Such new treatments might involve induction of repair using endogenous or exogenous stem cells or the reprogramming of the organ to reinitiate development. This review addresses the current state of understanding with respect to the ability of non-renal stem cell sources to influence renal repair, the existence of endogenous renal stem cells and the biology of normal renal repair in response to damage. Understanding repair options via an understanding of renal developmentThe prevalence and incidence of chronic kidney disease (CKD) is increasing at 6-8% per annum in the USA alone, largely as a result of increased prevalence of diabetes and obesity [1]. To understand what might be possible with respect to cellular therapies or regenerative medicine for the kidney, one first needs to consider what is understood about normal renal development and response to injury. The kidney has been classically regarded as an organ with minimal cellular turnover and no capacity for regeneration. The subsequent identification of stem cells in a number of such organs, including the brain, has challenged this view. However, the dogma remains that the kidney reaches a maximal complement of nephrons and then loses these over time [2]. This dogma is drawn from our understanding of the development of this organ. The progenitor population during developmentThe kidney is mesodermal in origin and develops from two populations derived from intermediate mesoderm, the ureteric bud (UB) and the metanephric mesenchyme (MM). While an even broader potential had been proposed [3], genetic and lineage analyses have confirmed that the MM gives rise to all portions of the nephron other than the collecting ducts and also gives rise to elements of the renal interstitium [4][5][6]. The UB gives rise to the ureter and collecting ducts only. The MM is apparently not homogeneous but forms condensed mesenchyme around the tips of the branching UB. This cap mesenchyme (CM) contains self-renewing progenitors capable of generating all cells of the nephron other than the collecting ducts via an initial mesenchyme-epithelial transition (MET) event throughout the prenatal developmental period [6]. The continued expression of the transcription factor Six2 in CM is required for maintenance of this stem cell population during kidney development [5]. As the UB branches and extends through the MM, individual MET events occur at the underside of each tip to form a new nephron [2]. This nephron endowment therefore proceeds from the centre of the kidney out to the periphery, with the CM stem cell field remaining on the outer edge of the expanding organ. Endowment of new nephrons is restricted to prenatal development in humans, while in rodents it persists only until the imm...

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The Contribution of Bone Marrow-Derived Cells to the Development of Renal Interstitial Fibrosis

Abstract: STEM CELLS 2007;25:697-706

Cited by 104 publications

References 55 publications

Selective delivery of IFN‐γ to renal interstitial myofibroblasts: a novel strategy for the treatment of renal fibrosis

Selective delivery of IFN‐γ to renal interstitial myofibroblasts: a novel strategy for the treatment of renal fibrosis

Renal fibrosis is attenuated by targeted disruption of K _Ca 3.1 potassium channels

Stem cell options for kidney disease

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The Contribution of Bone Marrow-Derived Cells to the Development of Renal Interstitial Fibrosis

Abstract: STEM CELLS 2007;25:697-706

Cited by 104 publications

References 55 publications

Selective delivery of IFN‐γ to renal interstitial myofibroblasts: a novel strategy for the treatment of renal fibrosis

Selective delivery of IFN‐γ to renal interstitial myofibroblasts: a novel strategy for the treatment of renal fibrosis

Renal fibrosis is attenuated by targeted disruption of K Ca 3.1 potassium channels

Stem cell options for kidney disease

Contact Info

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Renal fibrosis is attenuated by targeted disruption of K _Ca 3.1 potassium channels