Induced Pluripotent Stem Cells Reduce Progression of Experimental Chronic Kidney Disease but Develop Wilms’ Tumors

The therapeutic effect of induced pluripotent stem cells (iPSs) on the progression of chronic kidney disease (CKD) has not yet been demonstrated. In this study, we sought to assess whether treatment with iPSs retards progression of CKD when compared with bone marrow mesenchymal stem cells (BMSCs). Untreated 5/6 nephrectomized rats were compared with CKD animals receiving BMSCs or iPSs. Renal function, histology, immunohistochemistry, and gene expression were studied. Implanted iPSs were tracked by the SRY gene expression analysis. Both treatments minimized elevation in serum creatinine, significantly improved clearance, and slowed down progression of disease. The proteinuria was reduced only in the iPS group. Both treatments reduced glomerulosclerosis, iPSs decreased macrophage infiltration, and TGF-β was reduced in kidneys from the BMSC group. Both types of treatments increased VEGF gene expression, TGF-β was upregulated only in the iPS group, and IL-10 had low expression in both groups. The SRY gene was found in 5/8 rats treated with iPSs. These 5 animals presented tumors with histology and cells highly staining positive for PCNA and Wilms’ tumor protein antibody characteristics of Wilms’ tumor. These results suggest that iPSs may be efficient to retard progression of CKD but carry the risk of Wilms’ tumor development.

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Therapeutic Potential of Human Induced Pluripotent Stem Cells and Renal Progenitor Cells in Experimental Chronic Kidney Disease

10.21203/rs.3.rs-60474/v1 ◽

2020 ◽

Author(s):

Patrícia de Carvalho Ribeiro ◽

Fernando Henrique Lojudice ◽

Ida Maria Maximina Fernandes-Charpiot ◽

Maria Alice Sperto Ferreira Baptista ◽

Stanley de Almeida Araújo ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Stem Cells ◽

Kidney Disease ◽

Induced Pluripotent Stem Cells ◽

Pluripotent Stem Cells ◽

The Body ◽

Positive Staining ◽

Post Surgery ◽

Induced Pluripotent ◽

Renal Progenitor

Abstract BackgroundChronic Kidney Disease (CKD) is a global public health problem. Regenerative medicine using pluripotent stem cells represents an attractive therapeutic approach for the treatment of CKD.MethodsWe transplanted Mitomycin C (MMC)-treated human induced pluripotent stem cells (hiPSCs) and renal progenitors cells (RPCs) into a CKD rat model system. The RPCs and hiPSCs cells were characterized by immunofluorescence and qRT-PCR. Untreated 5/6 nephrectomized rats were compared to CKD animals receiving the same amount of MMC-treated hiPSCs or RPCs. Renal function, histology and immunohistochemistry were evaluated 45 days post-surgery. ResultsWe successfully generated hiPSCs from peripheral blood and differentiated them into RPCs expressing renal progenitor genes (PAX2, WT1, SIX2, and SALL1) and podocyte-related genes (SYNPO, NPHS1). RPCs also exhibited reduced OCT4 expression, confirming the loss of pluripotency. After cell transplantation into CKD rats, the body weight change was significantly increased in both hiPSC and RPC groups, in comparison with the control group. Creatinine clearance (CCr) was preserved only in the hiPSC group. Similarly, the number of macrophages in the kidneys of the hiPSC group reached a statistically significant reduction, when compared to control rats. Both treatments reduced positive staining for the marker α-smooth muscle actin. Histological features showed decreased tubulointerstitial damage (interstitial fibrosis and tubular atrophy) as well as a reduction in glomerulosclerosis in both iPSC and RPC groups.ConclusionsIn conclusion, we describe that both MMC-treated hiPSCs and RPCs exert beneficial effects in attenuating CKD progression. Both cell types were equally efficient to reduce histological damage and weight loss caused by CKD. hiPSCs seems to be more efficient than RPCs, possibly due to an anti-inflammatory mechanism triggered by hiPSCs. These results demonstrate that the use of MMC-treated hiPSCs and RPCs improve clinical and histological CKD parameters, avoided tumor formation, and therefore may be a promising cell therapy strategy for CKD.

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Therapeutic potential of human induced pluripotent stem cells and renal progenitor cells in experimental chronic kidney disease

10.21203/rs.3.rs-60474/v3 ◽

2020 ◽

Author(s):

Patrícia de Carvalho Ribeiro ◽

Fernando Henrique Lojudice ◽

Ida Maria Maximina Fernandes-Charpiot ◽

Maria Alice Sperto Ferreira Baptista ◽

Stanley de Almeida Araújo ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Stem Cells ◽

Kidney Disease ◽

Cell Therapy ◽

Induced Pluripotent Stem Cells ◽

Progenitor Cells ◽

Pluripotent Stem Cells ◽

Renal Progenitor Cells ◽

Induced Pluripotent ◽

Renal Progenitor

Abstract BackgroundChronic Kidney Disease (CKD) is a global public health problem. Cell therapy using pluripotent stem cells represents an attractive therapeutic approach for the treatment of CKD.MethodsWe transplanted Mitomycin C (MMC)-treated human induced pluripotent stem cells (hiPSCs) and renal progenitor cells (RPCs) into a CKD rat model system. The RPCs and hiPSCs cells were characterized by immunofluorescence and qRT-PCR. Untreated 5/6 nephrectomized rats were compared to CKD animals receiving the same amount of MMC-treated hiPSCs or RPCs. Renal function, histology and immunohistochemistry were evaluated 45 days post-surgery. ResultsWe successfully generated hiPSCs from peripheral blood and differentiated them into RPCs expressing renal progenitor genes (PAX2, WT1, SIX2, and SALL1) and podocyte-related genes (SYNPO, NPHS1). RPCs also exhibited reduced OCT4 expression, confirming the loss of pluripotency. After cell transplantation into CKD rats, the body weight change was significantly increased in both hiPSC and RPC groups, in comparison with the control group. Creatinine clearance (CCr) was preserved only in the hiPSC group. Similarly, the number of macrophages in the kidneys of the hiPSC group reached a statistically significant reduction, when compared to control rats. Both treatments reduced positive staining for the marker α-smooth muscle actin. Histological features showed decreased tubulointerstitial damage (interstitial fibrosis and tubular atrophy) as well as a reduction in glomerulosclerosis in both iPSC and RPC groups.ConclusionsIn conclusion, we describe that both MMC-treated hiPSCs and RPCs exert beneficial effects in attenuating CKD progression. Both cell types were equally efficient to reduce histological damage and weight loss caused by CKD. hiPSCs seems to be more efficient than RPCs, possibly due to a paracrine effect triggered by hiPSCs. These results demonstrate that the use of MMC-treated hiPSCs and RPCs improve clinical and histological CKD parameters, avoided tumor formation, and therefore may be a promising cell therapy strategy for CKD.

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Therapeutic potential of human induced pluripotent stem cells and renal progenitor cells in experimental chronic kidney disease

Stem Cell Research & Therapy ◽

10.1186/s13287-020-02060-4 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Patrícia de Carvalho Ribeiro ◽

Fernando Henrique Lojudice ◽

Ida Maria Maximina Fernandes-Charpiot ◽

Maria Alice Sperto Ferreira Baptista ◽

Stanley de Almeida Araújo ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Stem Cells ◽

Kidney Disease ◽

Cell Therapy ◽

Induced Pluripotent Stem Cells ◽

Progenitor Cells ◽

Pluripotent Stem Cells ◽

Renal Progenitor Cells ◽

Induced Pluripotent ◽

Renal Progenitor

Abstract Background Chronic kidney disease (CKD) is a global public health problem. Cell therapy using pluripotent stem cells represents an attractive therapeutic approach for the treatment of CKD. Methods We transplanted mitomycin C (MMC)-treated human induced pluripotent stem cells (hiPSCs) and renal progenitor cells (RPCs) into a CKD rat model system. The RPC and hiPSC cells were characterized by immunofluorescence and qRT-PCR. Untreated 5/6 nephrectomized rats were compared to CKD animals receiving the same amount of MMC-treated hiPSCs or RPCs. Renal function, histology, and immunohistochemistry were evaluated 45 days post-surgery. Results We successfully generated hiPSCs from peripheral blood and differentiated them into RPCs expressing renal progenitor genes (PAX2, WT1, SIX2, and SALL1) and podocyte-related genes (SYNPO, NPHS1). RPCs also exhibited reduced OCT4 expression, confirming the loss of pluripotency. After cell transplantation into CKD rats, the body weight change was significantly increased in both hiPSC and RPC groups, in comparison with the control group. Creatinine clearance (CCr) was preserved only in the hiPSC group. Similarly, the number of macrophages in the kidneys of the hiPSC group reached a statistically significant reduction, when compared to control rats. Both treatments reduced positive staining for the marker α-smooth muscle actin. Histological features showed decreased tubulointerstitial damage (interstitial fibrosis and tubular atrophy) as well as a reduction in glomerulosclerosis in both iPSC and RPC groups. Conclusions In conclusion, we describe that both MMC-treated hiPSCs and RPCs exert beneficial effects in attenuating CKD progression. Both cell types were equally efficient to reduce histological damage and weight loss caused by CKD. hiPSCs seem to be more efficient than RPCs, possibly due to a paracrine effect triggered by hiPSCs. These results demonstrate that the use of MMC-treated hiPSCs and RPCs improves clinical and histological CKD parameters, avoided tumor formation, and therefore may be a promising cell therapy strategy for CKD. Graphical abstract

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Therapeutic potential of human induced pluripotent stem cells and renal progenitor cells in experimental chronic kidney disease

10.21203/rs.3.rs-60474/v2 ◽

2020 ◽

Author(s):

Patrícia de Carvalho Ribeiro ◽

Fernando Henrique Lojudice ◽

Ida Maria Maximina Fernandes-Charpiot ◽

Maria Alice Sperto Ferreira Baptista ◽

Stanley de Almeida Araújo ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Stem Cells ◽

Kidney Disease ◽

Cell Therapy ◽

Induced Pluripotent Stem Cells ◽

Progenitor Cells ◽

Pluripotent Stem Cells ◽

Renal Progenitor Cells ◽

Induced Pluripotent ◽

Renal Progenitor

Abstract Background: Chronic Kidney Disease (CKD) is a global public health problem. Cell therapy using pluripotent stem cells represents an attractive therapeutic approach for the treatment of CKD.Methods: We transplanted Mitomycin C (MMC)-treated human induced pluripotent stem cells (hiPSCs) and renal progenitor cells (RPCs) into a CKD rat model system. The RPCs and hiPSCs cells were characterized by immunofluorescence and qRT-PCR. Untreated 5/6 nephrectomized rats were compared to CKD animals receiving the same amount of MMC-treated hiPSCs or RPCs. Renal function, histology and immunohistochemistry were evaluated 45 days post-surgery.Results: We successfully generated hiPSCs from peripheral blood and differentiated them into RPCs expressing renal progenitor genes (PAX2, WT1, SIX2, and SALL1) and podocyte-related genes (SYNPO, NPHS1). RPCs also exhibited reduced OCT4 expression, confirming the loss of pluripotency. After cell transplantation into CKD rats, the body weight change was significantly increased in both hiPSC and RPC groups, in comparison with the control group. Creatinine clearance (CCr) was preserved only in the hiPSC group. Similarly, the number of macrophages in the kidneys of the hiPSC group reached a statistically significant reduction, when compared to control rats. Both treatments reduced positive staining for the marker α-smooth muscle actin. Histological features showed decreased tubulointerstitial damage (interstitial fibrosis and tubular atrophy) as well as a reduction in glomerulosclerosis in both iPSC and RPC groups.Conclusions: In conclusion, we describe that both MMC-treated hiPSCs and RPCs exert beneficial effects in attenuating CKD progression. Both cell types were equally efficient to reduce histological damage and weight loss caused by CKD. hiPSCs seems to be more efficient than RPCs, possibly due to a paracrine effect triggered by hiPSCs. These results demonstrate that the use of MMC-treated hiPSCs and RPCs improve clinical and histological CKD parameters, avoided tumor formation, and therefore may be a promising cell therapy strategy for CKD.

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Faculty Opinions recommendation of Reduced ciliary polycystin-2 in induced pluripotent stem cells from polycystic kidney disease patients with PKD1 mutations.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718100719.793483452 ◽

2013 ◽

Author(s):

Angela Wandinger-Ness ◽

Heather Ward

Keyword(s):

Stem Cells ◽

Kidney Disease ◽

Induced Pluripotent Stem Cells ◽

Polycystic Kidney Disease ◽

Pluripotent Stem Cells ◽

Polycystic Kidney ◽

Induced Pluripotent

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Faculty Opinions recommendation of Large-Scale Profiling Reveals the Influence of Genetic Variation on Gene Expression in Human Induced Pluripotent Stem Cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727486306.793531822 ◽

2017 ◽

Author(s):

Vijay Tiwari ◽

Hyobin Jeong

Keyword(s):

Gene Expression ◽

Stem Cells ◽

Genetic Variation ◽

Induced Pluripotent Stem Cells ◽

Pluripotent Stem Cells ◽

Large Scale ◽

Induced Pluripotent

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T9. EPIGENETIC PROFILING IN SCHIZOPHRENIA DERIVED HUMAN INDUCED PLURIPOTENT STEM CELLS (HIPSCS) AND NEURONS

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa029.569 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S234-S234

Author(s):

Lorna Farrelly ◽

Shuangping Zhang ◽

Erin Flaherty ◽

Aaron Topol ◽

Nadine Schrode ◽

...

Keyword(s):

Gene Expression ◽

Mass Spectrometry ◽

Stem Cells ◽

Induced Pluripotent Stem Cells ◽

Pluripotent Stem Cells ◽

Neural Progenitor Cells ◽

Gene Expression Pattern ◽

Early Gene ◽

Label Free ◽

Induced Pluripotent

Abstract Background Schizophrenia (SCZ) is a severe psychiatric disorder affecting ~1% of the world’s population. It is largely heritable with genetic risk reflected by a combination of common variants of small effect and highly penetrant rare mutations. Chromatin modifications are known to play critical roles in the mediation of many neurodevelopmental processes, and, when disturbed, may also contribute to the precipitation of psychiatric disorders, such as SCZ. While a handful of candidate-based studies have measured changes in promoter-bound histone modifications, few mechanistic studies have been carried out to explore how these modifications may affect chromatin to precipitate behavioral phenotypes associated with the disease. Methods We applied an unbiased proteomics approach to evaluate the epigenetic landscape of SCZ in human induced pluripotent stem cells (hiPSC), neural progenitor cells (NPCs) and neurons from SCZ patients vs. matched controls. We utilized proteomics-based, label free liquid chromatography mass spectrometry (LC-MS/MS) on purified histones from these cells and confirmed our results by western blotting in postmortem SCZ cortical brain tissues. Furthermore we validated our findings with the application of histone interaction assays and structural and biophysical assessments to identify and confirm novel chromatin ‘readers’. To relate our findings to a SCZ phenotype we used a SCZ rodent model of prepulse inhibition (PPI) to perform pharmacological manipulations and behavioral assessments. Results Using label free mass spectrometry we performed PTM screening of hiPSCs, NPCs and matured neurons derived from SCZ patients and matched controls. We identified, amongst others, altered patterns of hyperacetylation in SCZ neurons. Additionally we identified enhanced binding of particular acetylation ‘reader’ proteins. Pharmacological inhibition of such proteins in an animal model of amphetamine sensitization ameliorated PPI deficits further validating this epigenetic signature in SCZ. Discussion Recent evidence indicates that relevance and patterns of acetylation in epigenetics advances beyond its role in transcription and small molecule inhibitors of these aberrant interactions hold promise as useful therapeutics. This study identifies a role for modulating gene expression changes associated with a SCZ epigenetic signature and warrants further investigation in terms of how this early gene expression pattern perhaps determines susceptibility or severity of the SCZ disease trajectory.

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