Cellular and Developmental Strategies Aimed at Kidney Tissue Engineering

Martovetsky, Gleb; Nigám, Sanjay K.

doi:10.1159/000360680

Cited by 5 publications

(3 citation statements)

References 37 publications

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“…5 and 6). Our results may also contribute to the future development of therapeutic strategies to enhance PT function and regenerative capacity as well as tissue engineering (reviewed in Nigam, 2013;Martovetsky and Nigam, 2014).…”

Section: Tablementioning

confidence: 87%

Kidney versus Liver Specification of SLC and ABC Drug Transporters, Tight Junction Molecules, and Biomarkers

Martovetsky

Bush

Nigám

2016

Drug Metabolism and Disposition

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The hepatocyte nuclear factors, Hnf1a and Hnf4a, in addition to playing key roles in determining hepatocyte fate, have been implicated as candidate lineage-determining transcription factors in the kidney proximal tubule (PT) [Martovetsky et. al., (2012) Mol Pharmacol 84:808], implying an additional level of regulation that is potentially important in developmental and/or tissue-engineering contexts. Mouse embryonic fibroblasts (MEFs) transduced with Hnf1a and Hnf4a form tight junctions and express multiple PT drug transporters (e.g., Slc22a6/Oat1, Slc47a1/Mate1, Slc22a12/Urat1, Abcg2/Bcrp, Abcc2/Mrp2, Abcc4/Mrp4), nutrient transporters (e.g., Slc34a1/NaPi-2, Slco1a6), and tight junction proteins (occludin, claudin 6, ZO-1/Tjp1, ZO-2/Tjp2). In contrast, the coexpression (with Hnf1a and Hnf4a) of GATA binding protein 4 (Gata4), as well as the forkhead box transcription factors, Foxa2 and Foxa3, in MEFs not only downregulates PT markers but also leads to upregulation of several hepatocyte markers, including albumin, apolipoprotein, and transferrin. A similar result was obtained with primary mouse PT cells. Thus, the presence of Gata4 and Foxa2/Foxa3 appears to alter the effect of Hnf1a and Hnf4a by an as-yet unidentified mechanism, leading toward the generation of more hepatocyte-like cells as opposed to cells exhibiting PT characteristics. The different roles of Hnf4a in the kidney and liver was further supported by reanalysis of ChIP-seq data, which revealed Hnf4a colocalization in the kidney near PT-enriched genes compared with those genes enriched in the liver. These findings provide valuable insight, not only into the developmental, and perhaps organotypic, regulation of drug transporters, drug-metabolizing enzymes, and tight junctions, but also for regenerative medicine strategies aimed at restoring the function of the liver and/or kidney (acute kidney injury, AKI; chronic kidney disease, CKD).

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Section: Tablementioning

confidence: 87%

Kidney versus Liver Specification of SLC and ABC Drug Transporters, Tight Junction Molecules, and Biomarkers

Martovetsky

Bush

Nigám

2016

Drug Metabolism and Disposition

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“…Some urologic diseases involving kidney, bladder and urethra are caused by specific tissue damage ( 7 – 9 ). Especially, stress urinary incontinence (SUI) is a common disorder mainly resulted from the support tissue deficiency, such as smooth muscle damage ( 10 ).…”

Section: Introductionmentioning

confidence: 99%

Small activating RNA induces myogenic differentiation of rat adipose-derived stem cells by upregulating MyoD

Wang

Chen

et al. 2015

Int. braz j urol.

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Purpose:RNA activation (RNAa) is a mechanism of gene activation triggered by promoter-targeted small double stranded RNAs (dsRNAs), also known as small activating RNAs (saRNAs). Myogenic regulatory factor MyoD is regarded as the master activator of myogenic differentiation cascade by binding to enhancer of muscle specific genes. Stress urinary incontinence (SUI) is a condition primarily resulted from urethral sphincter deficiency. It is thus expected that by promoting differentiation of adipose-derived stem cells (ADSCs) into myoblasts by activating MyoD gene through RNAa may offer benefits to SUI.Materials and Methods:Rats ADSCs were isolated, proliferated in vitro, and identified by flow cytometry. Purified ADSCs were then transfected with a MyoD saRNA or control transfected. Real-time polymerase chain reaction (RT-PCR) and western blotting were used to detect MyoD mRNA and protein expression, respectively. Immunocytochemical staining was applied to determine the expression of desmin protein in transfected cells. Cell viability was measured by using CellTiter 96® AQueous One Solution Cell Proliferation Assay kit.Results:Transfection of a MyoD saRNA (dsMyoD) into ADSCs significantly induced the expression of MyoD at both the mRNA and protein levels, and inhibited cell proliferation. Desmin protein expression was detected in dsMyoD treated ADSCs 2 weeks later.Conclusion:Our findings show that RNAa mediated overexpression of MyoD can promote transdifferentiation of ADSCs into myoblasts and may help treat stress urinary incontinence (SUI)–a condition primarily resulted from urethral sphincter deficiency.

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“…Whole organ transcriptomic approaches to study macrophage biology in solid tissues have critical limitations that arise from the cellular complexity of many organs including kidney. For instance, more than two dozen distinct cell types can be found in the kidney 17 and transcriptional analyses from whole tissue will thus only reflect a composite gene expression pattern of all cells, rather than of a single cell population. Laser-capture microdissection (LCM) and fluorescence-activated cell sorting (FACS) have been applied in solid tissues to enrich cell types of interest, but both require considerable, time-consuming manipulation of the tissue, which can significantly alter the naive expression profile of cells 18,19 .…”

mentioning

confidence: 99%

Development of a new macrophage-specific TRAP mouse (MacTRAP) and definition of the renal macrophage translational signature

Hofmeister

Thomaßen

Markert

et al. 2020

Sci Rep

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Tissue macrophages play an important role in organ homeostasis, immunity and the pathogenesis of various inflammation-driven diseases. One major challenge has been to selectively study resident macrophages in highly heterogeneous organs such as kidney. To address this problem, we adopted a Translational Ribosome Affinity Purification (TRAP)-approach and designed a transgene that expresses an eGFP-tagged ribosomal protein (L10a) under the control of the macrophage-specific c-fms promoter to generate c-fms-eGFP-L10a transgenic mice (Mac TRAP). Rigorous characterization found no gross abnormalities in Mac TRAP mice and confirmed transgene expression across various organs. Immunohistological analyses of Mac TRAP kidneys identified eGFP-L10a expressing cells in the tubulointerstitial compartment which stained positive for macrophage marker F4/80. Inflammatory challenge led to robust eGFP-L10a upregulation in kidney, confirming Mac TRAP responsiveness in vivo. We successfully extracted macrophage-specific polysomal RNA from Mac TRAP kidneys and conducted RNA sequencing followed by bioinformatical analyses, hereby establishing a comprehensive and unique in vivo gene expression and pathway signature of resident renal macrophages. In summary, we created, validated and applied a new, responsive macrophage-specific TRAP mouse line, defining the translational profile of renal macrophages and dendritic cells. This new tool may be of great value for the study of macrophage biology in different organs and various models of injury and disease.

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Cellular and Developmental Strategies Aimed at Kidney Tissue Engineering

Cited by 5 publications

References 37 publications

Kidney versus Liver Specification of SLC and ABC Drug Transporters, Tight Junction Molecules, and Biomarkers

Kidney versus Liver Specification of SLC and ABC Drug Transporters, Tight Junction Molecules, and Biomarkers

Small activating RNA induces myogenic differentiation of rat adipose-derived stem cells by upregulating MyoD

Development of a new macrophage-specific TRAP mouse (MacTRAP) and definition of the renal macrophage translational signature

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