Inhibition of Histone Deacetylase Activates Side Population Cells in Kidney and Partially Reverses Chronic Renal Injury

Imai, Naohiko; Hishikawa, Keiichi; Marumo, Takeshi; Hirahashi, Junichi; Inowa, Toshihiko; Matsuzaki, Yuji; Okano, Hideyuki; Kitamura, Tadaichi; Salant, David J.; Fujita, Toshiro

doi:10.1634/stemcells.2007-0049

Cited by 52 publications

(49 citation statements)

References 43 publications

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“…If SP cells exist in patients with renal failure, it may be possible to reverse the function by activating the cells, in situ, as in the case of the animal model. 6 Taken together, our results for the first time confirm the existence of SP cells, adult stem-like cells, in the human kidney, and suggest that the cells could be good targets for clinical regenerative medicine.…”

Section: Resultssupporting

confidence: 74%

“…3 Several groups have published reports regarding SP cells in the kidney. [3][4][5][6] Hishikawa and colleagues 4 reported that the SP cells isolated from the kidney of acute renal failure express high levels of renoprotective factors, such as hepatocyte growth factor, vascular endothelial growth factor, leukemia inhibitory factor and infusion of the renal SP cells improves renal function. The recent reports support the notion that the beneficial effects of tissue regeneration seem to be endocrine in nature.…”

Section: Editorial Commentmentioning

confidence: 99%

“…4,5 We recently reported that cell transplantation of kidney SP cells augmented the recovery of acute renal failure 4 and activation of the cells reversed chronic renal injury. 6 These results suggest that kidney SP cells are good targets for clinical renal regenerative therapy, but the existence of SP cells in human kidney has not been investigated. In this report, we optimize kidney SP cell analysis by using porcine kidney, and analyzed the existence of human kidney SP cells.…”

Section: Introductionmentioning

confidence: 98%

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Isolation and potential existence of side population cells in adult human kidney

Inowa¹,

Hishikawa

Takeuchi³

et al. 2008

Int J of Urology

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Abstract:The existence of adult stem-like cells such as side population (SP) cells is reported in various kinds of animal tissues, and we recently reported that mice kidney SP cells differentiate into multilineage. However, there has thus far been no report about human kidney SP cells. In the present study, we examined the existence of SP cells in human kidney tissue by using Hoechst 33342 staining and fluorescence-activated cell sorting analysis. We used porcine kidney tissue to optimize the analysis conditions for human tissue, and found that the SP population in human kidney was 1.3%. The existence of SP cells in human kidney suggests that the cells could be good targets for clinical renal regenerative medicine.

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Section: Resultssupporting

confidence: 74%

Section: Editorial Commentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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Isolation and potential existence of side population cells in adult human kidney

Inowa¹,

Hishikawa

Takeuchi³

et al. 2008

Int J of Urology

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“…All groups agree that, as for MSCs, SP cells shown multipotentiality and elicit an improvement in renal function via a humoral role, rather than by directly contributing to the replacement of renal tissue [73,74,76]. How this occurs is not clear, but the expression of renoprotective factors such as BMP7 has been reported to be higher in the SP than the non-SP fraction of the kidney [77].…”

Section: Progenitors Isolated Based Upon Cellular Behaviourmentioning

confidence: 80%

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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“…3 Interestingly, very recent studies also reported that treatment with HDAC inhibitors reduces epithelial-to-mesenchymal transition 15 and fibrosis in obstructive nephropathy, 16 regulates bone morphogenic protein 7 in the regenerative response to ischemia, 17 and prevents the progression of accelerated nephrotoxic serum nephritis toward glomerulosclerosis. 18 The central role of stem or progenitor cells in maintaining the integrity and functionality of organ tissues also suggests their manipulation might engender adverse effects. 12 Indeed, zebrafish larvae treated with HDAC inhibitors develop edema, 10 which suggests that deregulated expansion of renal progenitor cells can disrupt organ regeneration or function.…”

Section: From Proteus To Prometheusmentioning

confidence: 99%

From Proteus to Prometheus

Romagnani¹

2010

Journal of the American Society of Nephrology

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brane and/or transition fiber regulation might be detrimental for ciliogenesis and correct positioning, resulting in the observed phenotype of the double mutants. Many key questions remain unanswered. Even though MKS1 and MKS3 physically interact, it is unclear how they act to regulate ciliogenesis, cilia length control, or cilia number. In mammals, MKS3 function regulates the number of cilia on the apical membrane in kidney tissues in vivo and in vitro, and loss of MKS3 results in an increased number of cilia. The authors of this study do not comment on cilia numbers, which may reflect a difference between a mammalian and nematode role of MKS3. Along this line, MKS3 might play additional roles in mammals versus nematodes, on the basis of its differential localization. Elucidating the function of MKS3 will also require investigating its potential genetic interaction with other ciliopathy genes, which would give important insights into the understanding of the pathogenesis of the cystic phenotype.Several reports recently provided data indicating that phenotypic severity among MKS and NPHP is a consequence of mutational load, meaning that MKS and NPHP lie within a phenotypic continuum rather than represent multiple distinct clinical entities and that the sum of mutations in ciliary genes define the severity of the phenotype. Further studies of MKS3 in conjunction with other ciliary proteins are now required to unravel how different mutational loads can lead to the clinical variability observed in patients with MKS as well as other ciliopathies and identify further, second-site modifiers.This study by Williams et al. 12 offers a deeper understanding of the importance of mutational load on the presentation and severity of ciliopathies and expands the understanding of the synergistic interactions between ciliopathy genes. Further analysis will hopefully allow targeted therapies to alleviate the morbidity and mortality associated with these devastating diseases. proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia.

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Inhibition of Histone Deacetylase Activates Side Population Cells in Kidney and Partially Reverses Chronic Renal Injury

Abstract: ABSTRACT

Cited by 52 publications

References 43 publications

Isolation and potential existence of side population cells in adult human kidney

Isolation and potential existence of side population cells in adult human kidney

Stem cell options for kidney disease

From Proteus to Prometheus

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