Regrow or Repair: An Update on Potential Regenerative Therapies for the Kidney

Little, Melissa H.; Humphreys, Benjamin D.

doi:10.1681/asn.2021081073

Cited by 28 publications

(32 citation statements)

References 194 publications

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“…However, it is still difficult to fully reproduce the organ architecture and differentiation in vitro. With the discovery of iPS cells as a cell source for organ regeneration, advances in analytical technologies such as omics, and improvements in genome editing technology, technology has made great strides over the last 15 years [ 38 ]. Given the progress in the field of kidney regeneration, which requires regeneration of complex organ regeneration including urological tissues in vivo, I expect that hybrid organ regeneration technology based on chimera technology that borrows the developmental environment and structures of different animal species will facilitate the realization of 3D organ regeneration.…”

Section: Discussionmentioning

confidence: 99%

Generation of chimeric kidneys using progenitor cell replacement: Oshima Award Address 2021

Yamanaka

2022

Clin Exp Nephrol

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It is believed that the development of new renal replacement therapy (RRT) will increase treatment options for end-stage kidney disease and help reduce the mismatch between supply and demand. Technological advancement in the development of kidney organoids derived from pluripotent stem cells and xenotransplantation using porcine kidneys has been accelerated by a convergence of technological innovations, including the discovery of induced pluripotent stem cells and genome editing, and improvement of analysis techniques such as single-cell ribonucleic acid sequencing. Given the difficulty associated with kidney regeneration, hybrid kidneys are studied as an innovative approach that involves the use of stem cells to generate kidneys, with animal fetal kidneys used as a scaffold. Hybrid kidney technology entails the application of local chimerism for the generation of chimeric kidneys from exogenous renal progenitor cells by borrowing complex nephrogenesis programs from the developmental environment of heterologous animals. Hybrid kidneys can also utilize the urinary tract and bladder tissue of animal fetuses for urine excretion. Generating nephrons from syngeneic stem cells to increase self-cell ratio in xeno-tissues can reduce the risk of xeno-rejection. We showed that nephrons can be generated by ablation of host nephron progenitor cells (NPCs) in the nephron development region of animals and replacing them with exogenous NPCs. This progenitor cell replacement is the basis of hybrid kidney regeneration from progenitor cells using chimera technology. The goal of xeno-regenerative medicine using hybrid kidneys is to overcome serious organ shortage.

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Section: Discussionmentioning

confidence: 99%

Generation of chimeric kidneys using progenitor cell replacement: Oshima Award Address 2021

Yamanaka

2022

Clin Exp Nephrol

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“…Further, joint profiling of chromatin accessibility and gene expression of healthy human kidneys (specimens acquired after mass nephrectomy) using singlenucleus RNA-seq and single-nucleus ATAC-seq (assay for transposase-accessible chromatin with high-throughput sequencing) captures open chromatin sites (Muto et al, 2021). This study reveals a small subset of proximal tubular cells, characterized by VCAM1 expression and NF-κB activity, without a preceding episode of AKI, are transcriptionally similar to "failed repair" cells (Muto et al, 2021;Little and Humphreys, 2022). This subset of cells may also contribute to renal fibrosis.…”

Section: A Distinct Subset Of Proximal Tubular Cells Acquires a New P...mentioning

confidence: 90%

“…Acute injury in proximal tubules (PTs) peaks 48 h after injury, followed by tubular proliferation (Chang-Panesso et al, 2019). Evidence strongly supports the conclusion that resident tubular epithelial cells serve as the primary cellular source that replenishes lost tubular cells (Humphreys et al, 2008;Schiessl, 2020); however, the identity of intratubular cells responsible for the repair is still controversial (Schiessl, 2020;Little and Humphreys, 2022).…”

Section: Tubular Epithelial Cells Proliferate Through Dedifferentiati...mentioning

confidence: 98%

“…In contrast, a fixed population of Pax2 + /Kim-1intratubular proximal tubular progenitor cells undergo clonal expansion that mediates repair, serving as a model of the progenitor cells responsible for tubular repair (Lazzeri et al, 2018). However, a recent genetic lineage tracing analysis of dedifferentiated tubular cells expressing Kim-1 after injury shows the proliferative expansion of Kim-1 + dedifferentiated cells during tubular repair, suggesting that the proliferating cells after injury express the injury marker Kim-1, which does not support the contribution of Pax2 + /Kim-1progenitors to tubular repair (Chang-Panesso et al, 2019;Little and Humphreys, 2022).…”

Section: Tubular Epithelial Cells Proliferate Through Dedifferentiati...mentioning

confidence: 99%

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Epigenetic memory contributing to the pathogenesis of AKI-to-CKD transition

Tanemoto

Nangaku

Mimura

2022

Front. Mol. Biosci.

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Epigenetic memory, which refers to the ability of cells to retain and transmit epigenetic marks to their daughter cells, maintains unique gene expression patterns. Establishing programmed epigenetic memory at each stage of development is required for cell differentiation. Moreover, accumulating evidence shows that epigenetic memory acquired in response to environmental stimuli may be associated with diverse diseases. In the field of kidney diseases, the “memory” of acute kidney injury (AKI) leads to progression to chronic kidney disease (CKD); epidemiological studies show that patients who recover from AKI are at high risk of developing CKD. The underlying pathological processes include nephron loss, maladaptive epithelial repair, inflammation, and endothelial injury with vascular rarefaction. Further, epigenetic alterations may contribute as well to the pathophysiology of this AKI-to-CKD transition. Epigenetic changes induced by AKI, which can be recorded in cells, exert long-term effects as epigenetic memory. Considering the latest findings on the molecular basis of epigenetic memory and the pathophysiology of AKI-to-CKD transition, we propose here that epigenetic memory contributing to AKI-to-CKD transition can be classified according to the presence or absence of persistent changes in the associated regulation of gene expression, which we designate “driving” memory and “priming” memory, respectively. “Driving” memory, which persistently alters the regulation of gene expression, may contribute to disease progression by activating fibrogenic genes or inhibiting renoprotective genes. This process may be involved in generating the proinflammatory and profibrotic phenotypes of maladaptively repaired tubular cells after kidney injury. “Priming” memory is stored in seemingly successfully repaired tubular cells in the absence of detectable persistent phenotypic changes, which may enhance a subsequent transcriptional response to the second stimulus. This type of memory may contribute to AKI-to-CKD transition through the cumulative effects of enhanced expression of profibrotic genes required for wound repair after recurrent AKI. Further understanding of epigenetic memory will identify therapeutic targets of future epigenetic intervention to prevent AKI-to-CKD transition.

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“…Research on AKI and on the role of TEC must overcome three major challenges: a) finding a suitable way to study human disease pathomechanisms or effectively translate findings from mouse models to the human setting, b) provide clinicians with meaningful biomarkers to predict outcomes and c) understanding TEC repair to enable strategies to enhance regeneration and reduce scarring (7). It is reasonable to believe that answers to all three challenges may lie in the urine.…”

Section: Introductionmentioning

confidence: 99%

Urinary single-cell sequencing captures intrarenal injury and repair processes in human acute kidney injury

Klocke

Kim

Skopnik

et al. 2022

Preprint

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Acute kidney injury (AKI) is a major health issue, the outcome of which depends primarily on damage and reparative processes of tubular epithelial cells (TEC). Mechanisms underlying AKI remain incompletely understood, specific therapies are lacking and monitoring the course of AKI in clinical routine is confined to measuring urine output and plasma levels of filtration markers.Here we demonstrate feasibility and potential of a novel approach to assess the cellular and molecular dynamics of AKI by establishing a robust urine-to-single cell RNA sequencing (scRNAseq) pipeline for excreted kidney cells via flow cytometry sorting. We analyzed 42,608 single cell transcriptomes of 40 urine samples from 32 AKI patients and compared our data with reference material from human AKI post-mortem biopsies and published mouse data. We demonstrate that TEC transcriptomes mirror intrarenal pathology and reflect distinct injury and repair processes, including oxidative stress, inflammation, and tissue rearrangement. We also describe an AKI-specific abundant urinary excretion of progenitorlike cells.In conclusion, single cell transcriptomics of kidney cells excreted in urine provides non-invasive, unprecedented insight into cellular processes underlying AKI, thereby opening novel opportunities for target identification, AKI sub-categorization and monitoring of natural disease course and interventions.Graphical abstract

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Regrow or Repair: An Update on Potential Regenerative Therapies for the Kidney

Cited by 28 publications

References 194 publications

Generation of chimeric kidneys using progenitor cell replacement: Oshima Award Address 2021

Generation of chimeric kidneys using progenitor cell replacement: Oshima Award Address 2021

Epigenetic memory contributing to the pathogenesis of AKI-to-CKD transition

Urinary single-cell sequencing captures intrarenal injury and repair processes in human acute kidney injury

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