Kidney Cells Regeneration: Dedifferentiation of Tubular Epithelium, Resident Stem Cells and Possible Niches for Renal Progenitors

A kidney is an organ with relatively low basal cellular regenerative potential. However, renal cells have a pronounced ability to proliferate after injury, which undermines that the kidney cells are able to regenerate under induced conditions. The majority of studies explain yielded regeneration either by the dedifferentiation of the mature tubular epithelium or by the presence of a resident pool of progenitor cells in the kidney tissue. Whether cells responsible for the regeneration of the kidney initially have progenitor properties or if they obtain a “progenitor phenotype” during dedifferentiation after an injury, still stays the open question. The major stumbling block in resolving the issue is the lack of specific methods for distinguishing between dedifferentiated cells and resident progenitor cells. Transgenic animals, single-cell transcriptomics, and other recent approaches could be powerful tools to solve this problem. This review examines the main mechanisms of kidney regeneration: dedifferentiation of epithelial cells and activation of progenitor cells with special attention to potential niches of kidney progenitor cells. We attempted to give a detailed description of the most controversial topics in this field and ways to resolve these issues.

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Tubular cell-enriched subpopulation of primary renal cells improves survival and augments kidney function in rodent model of chronic kidney disease

AJP Renal Physiology ◽

10.1152/ajprenal.00221.2010 ◽

2010 ◽

Vol 299 (5) ◽

pp. F1026-F1039 ◽

Cited By ~ 45

Author(s):

Rusty Kelley ◽

Eric S. Werdin ◽

Andrew T. Bruce ◽

Sumana Choudhury ◽

Shay M. Wallace ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Kidney Function ◽

Transforming Growth Factor ◽

Kidney Tissue ◽

Tubular Cell ◽

Acute Injury ◽

Treatment Modalities ◽

Histological Evaluation ◽

Renal Cells

Established chronic kidney disease (CKD) may be identified by severely impaired renal filtration that ultimately leads to the need for dialysis or kidney transplant. Dialysis addresses only some of the sequelae of CKD, and a significant gap persists between patients needing transplant and available organs, providing impetus for development of new CKD treatment modalities. Some postulate that CKD develops from a progressive imbalance between tissue damage and the kidney's intrinsic repair and regeneration processes. In this study we evaluated the effect of kidney cells, delivered orthotopically by intraparenchymal injection to rodents 4–7 wk after CKD was established by two-step 5/6 renal mass reduction (NX), on the regeneration of kidney function and architecture as assessed by physiological, tissue, and molecular markers. A proof of concept for the model, cell delivery, and systemic effect was demonstrated with a heterogeneous population of renal cells (UNFX) that contained cells from all major compartments of the kidney. Tubular cells are known contributors to kidney regeneration in situ following acute injury. Initially tested as a control, a tubular cell-enriched subpopulation of UNFX (B2) surprisingly outperformed UNFX. Two independent studies (3 and 6 mo in duration) with B2 confirmed that B2 significantly extended survival and improved renal filtration (serum creatinine and blood urea nitrogen). The specificity of B2 effects was verified by direct comparison to cell-free vehicle controls and an equivalent dose of non-B2 cells. Quantitative histological evaluation of kidneys at 6 mo after treatment confirmed that B2 treatment reduced severity of kidney tissue pathology. Treatment-associated reduction of transforming growth factor (TGF)-β1, plasminogen activator inhibitor (PAI)-1, and fibronectin (FN) provided evidence that B2 cells attenuated canonical pathways of profibrotic extracellular matrix production.

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Dissecting hematopoietic and renal cell heterogeneity in adult zebrafish at single-cell resolution using RNA sequencing

Journal of Experimental Medicine ◽

10.1084/jem.20170976 ◽

2017 ◽

Vol 214 (10) ◽

pp. 2875-2887 ◽

Cited By ~ 54

Author(s):

Qin Tang ◽

Sowmya Iyer ◽

Riadh Lobbardi ◽

John C. Moore ◽

Huidong Chen ◽

...

Keyword(s):

Single Cell ◽

Natural Killer ◽

Progenitor Cells ◽

Rna Sequencing ◽

Immune Cell ◽

Interleukin 2 ◽

Kidney Cells ◽

Cell Heterogeneity ◽

Adult Zebrafish ◽

Hematopoietic Stem

Recent advances in single-cell, transcriptomic profiling have provided unprecedented access to investigate cell heterogeneity during tissue and organ development. In this study, we used massively parallel, single-cell RNA sequencing to define cell heterogeneity within the zebrafish kidney marrow, constructing a comprehensive molecular atlas of definitive hematopoiesis and functionally distinct renal cells found in adult zebrafish. Because our method analyzed blood and kidney cells in an unbiased manner, our approach was useful in characterizing immune-cell deficiencies within DNA–protein kinase catalytic subunit (prkdc), interleukin-2 receptor γ a (il2rga), and double-homozygous–mutant fish, identifying blood cell losses in T, B, and natural killer cells within specific genetic mutants. Our analysis also uncovered novel cell types, including two classes of natural killer immune cells, classically defined and erythroid-primed hematopoietic stem and progenitor cells, mucin-secreting kidney cells, and kidney stem/progenitor cells. In total, our work provides the first, comprehensive, single-cell, transcriptomic analysis of kidney and marrow cells in the adult zebrafish.

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Contribution of Resident Stem Cells to Liver and Biliary Tree Regeneration in Human Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms19102917 ◽

2018 ◽

Vol 19 (10) ◽

pp. 2917 ◽

Cited By ~ 20

Author(s):

Diletta Overi ◽

Guido Carpino ◽

Vincenzo Cardinale ◽

Antonio Franchitto ◽

Samira Safarikia ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Progenitor Cells ◽

Human Liver ◽

Progenitor Cell ◽

Biliary Tree ◽

Tree Regeneration ◽

Multipotent Stem Cells ◽

Resident Stem Cells ◽

Stem Cell Niches

Two distinct stem/progenitor cell populations of biliary origin have been identified in the adult liver and biliary tree. Hepatic Stem/progenitor Cells (HpSCs) are bipotent progenitor cells located within the canals of Hering and can be differentiated into mature hepatocytes and cholangiocytes; Biliary Tree Stem/progenitor Cells (BTSCs) are multipotent stem cells located within the peribiliary glands of large intrahepatic and extrahepatic bile ducts and able to differentiate into hepatic and pancreatic lineages. HpSCs and BTSCs are endowed in a specialized niche constituted by supporting cells and extracellular matrix compounds. The actual contribution of these stem cell niches to liver and biliary tree homeostatic regeneration is marginal; this is due to the high replicative capabilities and plasticity of mature parenchymal cells (i.e., hepatocytes and cholangiocytes). However, the study of human liver and biliary diseases disclosed how these stem cell niches are involved in the regenerative response after extensive and/or chronic injuries, with the activation of specific signaling pathways. The present review summarizes the contribution of stem/progenitor cell niches in human liver diseases, underlining mechanisms of activation and clinical implications, including fibrogenesis and disease progression.

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Hyperplasia after unilateral nephrectomy and role of excretory load in its production

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1961.201.3.517 ◽

1961 ◽

Vol 201 (3) ◽

pp. 517-522 ◽

Cited By ~ 21

Author(s):

David P. Simpson

Keyword(s):

Cell Division ◽

Peritoneal Cavity ◽

Kidney Tissue ◽

Work Load ◽

Unilateral Nephrectomy ◽

Kidney Cells ◽

Per Se

Using P32 uptake in DNA nucleotides as an index of mitoses, hyperplasia in the kidney has been studied in rats both after unilateral nephrectomy and after transplantation of one ureter into the peritoneal cavity. In the latter group, in which the excretory load on each kidney was increased without removing any kidney tissue, no increase in P32 uptake was present 48 hr after operation, whereas in unilaterally nephrectomized animals the P32 uptake was doubled at this time, compared to control animals. These results are interpreted as indicating that the increased work load on the remaining kidney after unilateral nephrectomy is not responsible for stimulating cell division. It is suggested that hyperplasia under these conditions is probably a result of the decrease in the number of kidney cells per se.

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P0529THE DIFFERENCE IN DIETARY RESTRICTION-INDUCED NEPHROPROTECTIVE MECHANISMS IN YOUNG AND OLD ANIMALS

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p0529 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Nadezda Andrianova ◽

Ljubava Zorova ◽

Irina Pevzner ◽

Vasily Popkov ◽

Denis Silachev ◽

...

Keyword(s):

Lipid Peroxidation ◽

Dietary Restriction ◽

Kidney Tissue ◽

Kidney Injury ◽

Male Rats ◽

Kidney Cells ◽

Lipid Peroxidation Products ◽

Kidney Slices ◽

Young Rats ◽

Old Rats

Abstract Background and Aims Acute kidney injury (AKI) is a widespread disease affecting mostly old people. Dietary restriction (DR), based on the reduction of food intake, is believed to be one of the most efficient approaches ameliorating damage in different pathological conditions including age-associated diseases. The aim of the study was to investigate the protective mechanisms of DR in the model of AKI in young and old rats. Method All experiments were made on young (3-4 months) and old (22-24 months) male rats. DR was performed by limiting the amount of food for 35% of the ad libitum (AL) daily intake. Since earlier, we showed ineffectiveness of 4-weeks DR in old rats, in this study we applied 35% DR lasting 8 weeks for old rats and 4 weeks for young rats. During DR, we registered the weight loss and measured the level of adiponectin, as this hormone is closely associated with adipose tissue metabolism. Renal ischemia/reperfusion (I/R) was used as a model of ischemic AKI. I/R was performed by clamping the left renal pedicle for 40 minutes followed by reperfusion with simultaneous contralateral nephrectomy. The severity of AKI was evaluated by measuring blood urea nitrogen (BUN), serum creatinine (SCr) and the levels of protein biomarkers of AKI (NGAL and L-FABP) in urine. Proliferation in kidney epithelium in response to I/R was analyzed by PCNA protein level in kidney tissue. We evaluated the function of mitochondria by measuring TMRE/MitoTracker Green ratio in vital kidney slices; in kidney homogenates, we also analyzed levels of Bcl-XL and Bcl-XS proteins. The production of reactive oxygen species (ROS) was evaluated by staining vital kidney slices with DCF. The content of lipid peroxidation products was measured using Image-iT Lipid Peroxidation Kit, and the level of carbonylated proteins was determined by OxyBlot Protein Oxidation Detection Kit. The activation of autophagic-lysosomal system was estimated by western blotting to LC3 II/LC3 I ratio and LAMP1 level, as well as by staining vital kidney slices with LysoTracker Green probe. Results The body weight of rats during DR dropped as far as 20% by the end of 4 weeks in young rats and 30% by the end of 8 weeks in old rats. Nevertheless, adiponectin concentration elevated during DR only in the serum of young rats. DR strongly influenced mitochondria function, in particular, elevated mitochondrial membrane potential both in kidney cells of young and old rats. DR also resulted in increasing the Bcl-XL level. We revealed the decrease of ROS and lipid peroxidation products in vital kidney slices, but only in kidneys of young rats. However, DR reduced the content of carbonyl groups more than 2 times in animals of both ages. We showed that activation of autophagy in response to DR and I/R occurred only in the kidneys of young rats, indicating deterioration of autophagy signaling in old animals. We also found that 48 h after I/R PCNA level increased 19 times in young kidney, although old rats showed only 4-fold elevation of kidney cells proliferation. Estimation of kidney injury markers (NGAL, L-FABP) in urine revealed that 2-month DR led to some protection in old rats. Nonetheless, despite all positive alterations in kidney tissue of old rats, DR was not able to ameliorate impairment of kidney function after I/R, whereas all young rats showed significant improvement of SCr and BUN levels. Conclusion Short-term DR has a significant nephroprotective effect against renal I/R in young rats. Old animals require longer periods of food restriction, after which some protective alterations are observed. We propose, protection of kidney in old and young rats is implemented through slightly different mechanisms and some of them are missing in old animals.

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NEW TARGETS FOR THE STUDIES OF BIOMECHANICAL, ENDOCRINOLOGIC, GENETIC AND PHARMACEUTICAL EFFECTS ON BONES: BONE'S "NEPHRON EQUIVALENTS", MUSCLE, NEUROMUSCULAR PHYSIOLOGY

Journal of Musculoskeletal Research ◽

10.1142/s0218957700000173 ◽

2000 ◽

Vol 04 (02) ◽

pp. 67-84 ◽

Cited By ~ 1

Author(s):

Harold M. Frost

Keyword(s):

Common Sense ◽

Plate Tectonics ◽

Interdisciplinary Communication ◽

Renal Physiology ◽

Kidney Cells ◽

Renal Cells ◽

Effector Cells ◽

The World ◽

Utah Paradigm ◽

Bone Physiology

As age, experience and common sense look at biomechanical, hormonal, genetic and other roles in bone physiology and its disorders, two questions can arise: (a) How did we fail? (b) How could we make it better? The acerbic Sam Johnson said that to teach new things, we should use examples of already known ones. If so, an analogy might help to clarify this article's message for people who work with bones and their disorders. Assume this: (a) Mythical physiologists were taught that renal physiology depends on "kidney cells" but were taught nothing about nephrons; (b) so they explained renal health and disorders in those terms. (c) For many decades, they "knew" that view was correct (as the ancients "knew" the world was flat). (d) But then others described nephrons and some errors their properties revealed in those views about renal physiology; (e) so controversies began. Today, an analogous situation confronts real biomechanicians and physiologists. (i) Most of them were taught that osteoblasts and osteoclasts (bone's "effector cells") explain bone physiology without "nephron-equivalent" input, so they explained bone disorders and mechanical effects in those terms. (ii) Yet nephron-equivalent mechanisms and functions, including biomechanical ones, in bones have the same operational relationship to their cells, health and disorders as nephrons and their functions do to renal cells, health and disorders. (iii) Adding that knowledge to former views led to the Utah paradigm of skeletal physiology. It also revealed errors in many former views about bone physiology; (iv) so real controversies have begun. Biomechanicians, physiologists, clinicians and pharmacologists from whom poor interdisciplinary communication hid that paradigm could think the view in (i) above remains valid, and keep analyzing data and designing studies within its constraints. Like Wegner's idea of plate tectonics in geology, the Utah paradigm came before its field was ready, so others fought it. But while the plate-tectonics war was won, it has just begun for the Utah paradigm. This article reviews how such things could apply to bone and some of their implications. Its conclusion offers succinct answers to the italicized questions above.

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Potential use of stem or progenitor cells for kidney regeneration

Nature Reviews Nephrology ◽

10.1038/nrneph.2013.257 ◽

2013 ◽

Vol 10 (2) ◽

pp. 67-68 ◽

Cited By ~ 7

Author(s):

Luigi Biancone ◽

Giovanni Camussi

Keyword(s):

Progenitor Cells ◽

Kidney Regeneration ◽

Potential Use

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Pattern of renal pathology in fish from Al-Hassa waterways, Saudi Arabia

Indian Journal of Animal Research ◽

10.18805/ijar.b-910 ◽

2018 ◽

Author(s):

Ashraf Abdel Moneim ◽

Omar Elmenshawy ◽

Mohamed Al Kahtani ◽

Abdalla Sayed ◽

Manal Alfwuaires

Keyword(s):

Saudi Arabia ◽

Kidney Tissue ◽

Tubular Epithelium ◽

Histological Changes ◽

Histological Damage ◽

Fish Samples ◽

Histopathological Studies ◽

Relative Differences ◽

Glomerular Capillaries

Pollution of aquatic environment is a great concern worldwide. The teleostean kidney is one of the first organ to be affected by contaminants in water. The aim of this study is to assess histological changes of Oreochromis niloticus kidney collected from spring canals in Al-Hassa, Saudi Arabia. We report histological alterations in the kidney tissue of fish collected from three sites, namely Al-Jawhariya (site #1), Um-Sabah (site #2) and Al-Khadoud spring (site #3). The histopathological studies revealed relative differences in the severity of organ lesions among the three sites. The overall results showed that kidney architecture of fish samples was markedly disrupted. The major symptoms were dilation of the glomerular capillaries, reduction of Bowman’s space, degeneration of tubular epithelium, tubule cast deposition, and accumulation of pigmented macrophages (i.e., melanomacrophages). The histological damage in the kidney of O. niloticus is an evidence of the poor environmental quality of these spring canals. It appears that these wetland areas are still threatened by human activities and environmental degradation.

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Activated Hedgehog-GLI Signaling Causes Congenital Ureteropelvic Junction Obstruction

Journal of the American Society of Nephrology ◽

10.1681/asn.2017050482 ◽

2017 ◽

Vol 29 (2) ◽

pp. 532-544 ◽

Cited By ~ 6

Author(s):

Sepideh Sheybani-Deloui ◽

Lijun Chi ◽

Marian V. Staite ◽

Jason E. Cain ◽

Brian J. Nieman ◽

...

Keyword(s):

Smooth Muscle ◽

Progenitor Cells ◽

Hedgehog Signaling ◽

Ureteropelvic Junction Obstruction ◽

Lineage Tracing ◽

Ureteropelvic Junction ◽

Genetic Lineage ◽

Intermediate Mesoderm ◽

Renal Progenitors ◽

Deficient Mice

Intrinsic ureteropelvic junction obstruction is the most common cause of congenital hydronephrosis, yet the underlying pathogenesis is undefined. Hedgehog proteins control morphogenesis by promoting GLI-dependent transcriptional activation and inhibiting the formation of the GLI3 transcriptional repressor. Hedgehog regulates differentiation and proliferation of ureteric smooth muscle progenitor cells during murine kidney-ureter development. Histopathologic findings of smooth muscle cell hypertrophy and stroma-like cells, consistently observed in obstructing tissue at the time of surgical correction, suggest that Hedgehog signaling is abnormally regulated during the genesis of congenital intrinsic ureteropelvic junction obstruction. Here, we demonstrate that constitutively active Hedgehog signaling in murine intermediate mesoderm–derived renal progenitors results in hydronephrosis and failure to develop a patent pelvic-ureteric junction. Tissue obstructing the ureteropelvic junction was marked as early as E13.5 by an ectopic population of cells expressing Ptch2, a Hedgehog signaling target. Constitutive expression of GLI3 repressor in Ptch1-deficient mice rescued ectopic Ptch2 expression and obstructive hydronephrosis. Whole transcriptome analysis of isolated Ptch2+ cells revealed coexpression of genes characteristic of stromal progenitor cells. Genetic lineage tracing indicated that stromal cells blocking the ureteropelvic junction were derived from intermediate mesoderm–derived renal progenitors and were distinct from the smooth muscle or epithelial lineages. Analysis of obstructive ureteric tissue resected from children with congenital intrinsic ureteropelvic junction obstruction revealed a molecular signature similar to that observed in Ptch1-deficient mice. Together, these results demonstrate a Hedgehog-dependent mechanism underlying mammalian intrinsic ureteropelvic junction obstruction.

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