SOX9 switch links regeneration to fibrosis at the single-cell level in mammalian kidneys

doi:10.1126/science.add6371

. 2024 Feb 23;383(6685):eadd6371.

doi: 10.1126/science.add6371. Epub 2024 Feb 23.

SOX9 switch links regeneration to fibrosis at the single-cell level in mammalian kidneys

Shikhar Aggarwal^#^{1

2}, Zhanxiang Wang^#^{1

2}, David Rincon Fernandez Pacheco^#^{1

2}, Anna Rinaldi³, Alex Rajewski⁴, Jasper Callemeyn⁵, Elisabet Van Loon⁵, Baptiste Lamarthée⁵, Ambart Ester Covarrubias⁶, Jean Hou⁷, Michifumi Yamashita⁷, Haruhiko Akiyama⁸, S Ananth Karumanchi^{2

6}, Clive N Svendsen^{1

2}, Paul W Noble⁹, Stanley C Jordan⁶, Joshua J Breunig^{1

2}, Maarten Naesens⁵, Pietro E Cippà^{3

10}, Sanjeev Kumar^{1

2

6}

Affiliations

¹ Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
² Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
³ Division of Nephrology, Ente Ospedaliero Cantonale, CH-6900 Lugano, Switzerland.
⁴ Applied Genomics, Computation, and Translational Core, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁵ Department of Microbiology, Immunology and Transplantation, KU Leuven, BE-3000 Leuven, Belgium.
⁶ Division of Nephrology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁷ Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁸ Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
⁹ Division of Pulmonary and Critical Care Medicine, Department of Medicine, Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
¹⁰ Faculty of Biomedical Sciences, Università della Svizzera Italiana, CH-6900 Lugano, Switzerland.

^# Contributed equally.

PMID: 38386758
PMCID: PMC11345873
DOI: 10.1126/science.add6371

SOX9 switch links regeneration to fibrosis at the single-cell level in mammalian kidneys

Shikhar Aggarwal et al. Science. 2024.

. 2024 Feb 23;383(6685):eadd6371.

doi: 10.1126/science.add6371. Epub 2024 Feb 23.

Authors

Affiliations

¹ Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
² Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
³ Division of Nephrology, Ente Ospedaliero Cantonale, CH-6900 Lugano, Switzerland.
⁴ Applied Genomics, Computation, and Translational Core, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁵ Department of Microbiology, Immunology and Transplantation, KU Leuven, BE-3000 Leuven, Belgium.
⁶ Division of Nephrology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁷ Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁸ Department of Orthopaedic Surgery, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
⁹ Division of Pulmonary and Critical Care Medicine, Department of Medicine, Women's Guild Lung Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
¹⁰ Faculty of Biomedical Sciences, Università della Svizzera Italiana, CH-6900 Lugano, Switzerland.

^# Contributed equally.

PMID: 38386758
PMCID: PMC11345873
DOI: 10.1126/science.add6371

Abstract

The steps governing healing with or without fibrosis within the same microenvironment are unclear. After acute kidney injury (AKI), injured proximal tubular epithelial cells activate SOX9 for self-restoration. Using a multimodal approach for a head-to-head comparison of injury-induced SOX9 lineages, we identified a dynamic SOX9 switch in repairing epithelia. Lineages that regenerated epithelia silenced SOX9 and healed without fibrosis (SOX9^on-off). By contrast, lineages with unrestored apicobasal polarity maintained SOX9 activity in sustained efforts to regenerate, which were identified as a SOX9^on-on Cadherin6^pos cell state. These reprogrammed cells generated substantial single-cell WNT activity to provoke a fibroproliferative response in adjacent fibroblasts, driving AKI to chronic kidney disease. Transplanted human kidneys displayed similar SOX9/CDH6/WNT2B responses. Thus, we have uncovered a sensor of epithelial repair status, the activity of which determines regeneration with or without fibrosis.

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Figures

**Fig. 1.. scRNA-seq reveals a dynamic SOX9/CDH6 switch within the repairing nephron epithelium.**
(A) Identification of a dynamic Sox9 switch. Shown are the schema of lineage-tracing of injury-induced Sox9^pos cells and co-immunoanalysis for SOX9 and the basolateral polarity marker ATP1A1, showing that cells with disrupted basolateral polarity activated SOX9. Note the co-localization of tdT with SOX9^pos cells at 48 hours after IRI (IRI 48 hours: Sox9^on cells, yellow arrows). By day 10 after IRI, the lineage of Sox9^on cells that restored basolateral polarity had silenced SOX9 (Sox9^on-off cell state, regenerated epithelia), whereas the lineage with unrestored ATP1A1 maintained SOX9 activity (Sox9^on-on cells, yellow arrows). (B) Schema of isolating single cells to compare IRI 48 hours *Sox9*^pos (n = 2) versus day 10 *Sox9*^pos cells, with dot plot showing average gene expression values and percentage of cells expressing cell-type- specific markers of differentiation, injury (*Havcr1* and *Lcn2*), and repair (*Sox9*) response. (C) Time-resolved UMAP projection of *Sox9*^pos cells within the proximal tubule cluster. Arrows show distinct clusters at day 10 after IRI containing *Sox9*^pos cells compared with 48 hours after IRI. (D) Topmost enriched GO cellular components and biological processes in IRI day 10 *Sox9*^pos cells versus 48 hour *Sox9*^pos cells. (E) Heatmap of genes driving the GO terms. Shown is the enrichment of epithelial cell-cell adhesion machinery, including *Cdh6*, within day 10 *Sox9*^pos cells. (F) Time-resolved UMAP projection of *Cdh6*^pos cells (arrows) within the PT cluster. (G and H) Co-immunostaining for CDH6 and SOX9 (G) and ATP1A1 (H) showing CDH6 expression restricted to day 10 SOX9^pos cells (G) and to the Sox9 lineage with unrestored ATP1A1-based basolateral polarity versus the lineage that restored polarity (H), indicating that CDH6 demarcates Sox9^on-on cells (SOX9^posCDH6^pos cell state). (I) Co-immunostaining for SOX9 and the epithelial tight junction marker ZO-1 and immunoblot for SOX9 and CDH6 showing that cells that lacked cell-cell contact (subconfluent state) activated SOX9 and CDH6, which waned upon restoration of tight junctions (confluent monolayer). Box inset highlights the region depicted at high magnification. All n = 3 animals per time point unless otherwise stated. Data are shown as mean ± SEM. Scale bars, 100 μm. For total cells counted, see table S1.

**Fig. 2.. CDH6 status is tightly linked to repair with or without αSMA^pos myofibroblast response through single-cell Wnt activity.**
(A) Schema of lineage-tracing of IRI-induced Sox9^pos cells and co-immunostaining showing αSMA^pos myofibroblasts adjacent to SOX9^postdT^pos cells (Sox9^on-on cells, arrows) but no detectable αSMA activity around the Sox9^on-off cells (arrow). Left and right magnified panels correspond to the foci highlighted by corresponding left and right box insets. (B) Co-immunoanalysis showing αSMA^pos myofibroblasts encasing the CDH6^pos Sox9 lineages at single-cell spatial distance; by contrast, the paucity of such response around the CDH6^negSox9-lineage can be observed (arrow). Circle and box highlight such foci, with the magnified panel corresponding to the foci highlighted by the box inset. (C) Schemas for purifying *Slc34a1*^pos normal PTECs (control tdT^pos cells) and Sox9^pos cells 48 hours and day 14 after IRI and principal components analysis (PCA) plot showing distinct transcriptomic profiles of purified tdT^pos cells. *Sox9* transcripts were enriched in purified tdT^pos cells. (D) qPCR of purified tdT^pos cells confirming *Sox9* and *Cdh6* enrichment. (E) UMAP projections for *Sox11* at 48 hours and day 10 after IRI. Arrows highlight the distinct day 10 cluster composed of these cells. Single *Sox9*^pos and *Cdh6*^pos cells also contributed to this cluster (Fig. 1, B and E). (F) Volcano plot demonstrating enrichment of Wnt ligands within day 14 versus 48 hour tdT^pos cells. (G) UMAP projections for *Wnt4* and *Wnt7b* at 48 hours and day 10 after IRI. Arrows highlight the distinct day 10 cluster, which contained such single *Wnt4*^pos and *Wnt7b*^pos cells. Note that the same distinct cluster was composed of day 10 *Sox9*^pos, *Cdh6*^pos, and *Sox11*^pos cells [see also Fig. 1, B and E, and this figure (E)]. (H) Upset plot analysis of scRNAseq datasets showing subset of single *Cdh6*^pos cells enriched with *Wnt4*, including *Cdh6*^posSox11^pos subsets. (I) qPCR of purified tdT^pos cells confirming *Wnt4* enrichment in day 14 post-IRI tdT^pos cells versus their 48-hour counterparts. (J) Schema for labeling early *Axin2*^pos cells after IRI and immunoanalysis for CDH6 showing co-localization of tdT^pos and GFP^pos cells with tdT^posGFP^pos cells located adjacent to CDH6^pos subsets. Circles and box highlight single-cell, biologically active Wnt-enriched niches robustly linked with subsets of CDH6^pos cells. Magnified panels correspond to the foci highlighted by box inset. All n = 3 animals per time point unless otherwise stated. Data are shown as mean ± SEM. Scale bars, 100 μm. For total cells counted, see table S1.

**Fig. 3.. Sox9^on-on cell state is the main driver of myofibroblast formation and maintenance.**
(A to C) Schema of *Wls* removal from Sox9^on-on cells, outer medullary region representative image, and blinded co-immunoanalysis for SOX9 and αSMA (n = 5 animals/group). No difference can be seen in Sox9^on-on cells between the two groups (B). The mosaic tissue–damaged microenvironment displayed significantly (P < 0.01) reduced αSMA^pos myofibroblasts adjacent to tdT^pos demarcated *Wls-*KO tubules (arrows) versus tdT^neg tubules with intact *Wls* [(C), arrowheads]. (D) Schema of isolating early *Axin2*^pos cells after IRI with FACS plot showing that nearly all tdT^pos cells co-expressed GFP. (E) PCA plot of purified tdT^posGFP^pos and tdT^negGFP^pos cells. (F) GO analysis showing Wnt pathway among the top 10 terms, confirming that *Axin2*^pos cells demarcated early WRCs. (G and H) Volcano plot showing the molecular signature of early WRCs, with qPCR confirming *Axin2* enrichment within tdT^posGFP^pos cells, thus validating reporter animals. (I) UMAP projection of *Axin2*, *Nkd1*, and *Nkd2* cells. Such cells were within the same *Pdgfrb*^posCola1^posCol3a1^pos cluster (see also fig. S9). (J) Experimental outline of removal of Sox9^on-on activity during the AKI to CKD transition. (K and L) Trichrome staining (K) and quantitative scores of interstitial fibrosis (L) (blinded analysis, n = 5 *Sox9-Ctrl* and 6 *Sox9-cKO* animals). (M and N) Co-immunostaining for SOX9, KIM1, and αSMA (M) and blinded co-immunoanalysis showing head-head comparison between KIM1⁺ regions for αSMA activity (N) in *Sox9-cKO* versus *Sox9-Ctrl* animals. (O) qPCR analysis of genes associated with fibrosis in the kidneys from *Sox9-cKO* versus *Sox9-Ctrl* animals. (P and Q) Western blot confirming SOX9 knock-down in subconfluent primary TECs (P), with qPCR showing *Sox9* and *Wnt4* down-regulation (Q). (R and S) RNAscope image (R) and analysis (S) showing significant (P < 0.01) *Wnt4* reduction. (T) qPCR analysis of Wnts under scrutiny and *Axin2*, *Nkd1*, and *Nkd2* in the kidneys from *Sox9-cKO* versus *Sox9-Ctrl.* All images are representative images. Data are shown as mean ± SEM. *P < 0.05, **P < 0.01 unpaired two-sided Student’s t test; ***P < 0.01, paired Student’s t test. Scale bars in whole scanned images [(K) and (R)], 1000 μm; all others, 100 μm. For total cells counted, see table S1.

**Fig. 4.. Epigenetic reprogramming of single Sox9^on-on nuclei to a nephron progenitor–like state contrasts with the Sox9^on-off counterpart, which reverts to normal PTEC.**
(A) Schema of the workflow to obtain single nuclei of the FACS-enriched tdT^pos Sox9-descendants at day 10 after injury. Rectangle (inset) highlights the dissected region showing the inner cortices and outer medulla, the site of relatively extensive PTEC loss. (B) Integration of scRNA-seq and snATAC-seq showing the cellular identity of single-tdT^pos nuclei (n = 2 animals). (C) Identification of *Sox9*^on-on and *Sox9*^on-off single nuclei: Chromatin accessibility revealing clustering of tdT^pos descendants based on relatively open and closed chromatin accessibility state of *Sox9*. *Sox9*^on-off nuclei exhibited open chromatin accessibility for *Hnf4a*, a known marker of healthy, mature PTECs, suggesting that the Sox9-lineage that regenerated normal PTECs closed chromatin accessibility for *Sox9*. (D) UMAP representation of chromatin accessibility analysis showing the relatively open chromatin state of *Havcr1*, *Wnt7b*, *Wnt4*, and *Cdh6* versus their accessibility state in *Sox9*^on-off nuclei. (E and F) Sox9 trajectory analysis with scRNAseq-imputed gene expression (E) and pseudotime (F) scale showing the Sox9^on-on → Sox9^on-off transition. (G) Heatmaps of cross-platform linked genes involved in the transcriptional cascade during Sox9^on-on → Sox9^on-off transition. Note that the highlighted genes in Sox9^on-on nuclei are linked with tissue development and/or nephrogenesis, and the *Sox9*^on-off nuclei displayed open chromatin accessibility for *Hnf4β*, another known marker of healthy, mature PTECs in addition to *Hnf4a.* (H) Schema of EDU regime and co-immunostaining for SOX9 and EDU showing SOX9^postdT^posEDU^pos cells. Two representative images are shown, with the lower panel demonstrating a cluster of such cells. n = 3 animals. (I and J) Co-immunostaining for SMARCC1 and CDH6 showing SMARCC1 expression confined to day 10 CDH6^pos Sox9 lineage cells (I), and RUNX1 and SOX9 co-immunostaining showing RUNX1 restricted to Sox9^on-on versus Sox9^on-off lineage (J) as predicted by (G), thus validating Sox9 lineage-specific snATAC-seq datasets. n = 2 animals. Scale bars, 100 μm.

**Fig. 5.. Human renal allografts display dynamic *SOX9/CDH6/WNT2B* activity, with CDH6^pos cells demarcating SOX9^on-on activity and fibrotic foci.**
(A) Co-immunostaining for SOX9 and LTL in biopsies obtained before implantation (uninjured) and IRI-induced AKI after transplantation (same allograft) showing early SOX9 activation. (B) Box plot showing *SOX9* levels at different time points within kidney transplant protocol biopsies (n = 163). (C and D) Dot plots (C) and box plots (D) showing categorization of patients and kidney function according to *SOX9* levels at 1 year (comparison by Mann-Whitney U test; n = 35). (E) Histograms showing the number of patients with different degrees of kidney fibrosis, as estimated by ci-score according to Banff classification (comparison by chi-square test; n = 39). (F) Box plot showing *SOX9* and *CDH6* levels categorized according to a previously reported model discriminating the transcriptome of kidney transplant biopsies in successful repair (1), transition to chronic injury (2), or CKD (3). LD, biopsies obtained from living donors at the time of transplantation (49). (G) Heatmap showing expression correlation of genes of interest at 3 and 12 months after transplantation (Spearman r correlation coefficient; n = 72). Arrows highlight the identified molecular signatures of *SOX9/CDH6/WNT*, including *AXIN2* and *NKD1* in human kidneys. Note that *CDH6* is the topmost correlated gene. (H) UMAP showing distinct PTEC clustering (29,180 genes × 24,070 cells). (I) Dot plot showing average gene expression values and percentage of cells expressing markers of differentiation and injury, *SOX9* and *CDH6*, by each identified cluster of PTECs. Cluster 8 consisted of *SOX9*-, *CDH6*-, and *WNT2B*-expressing cells (see also figs. S22, C to E, and S23). (J) Feature plot displaying the normalized transcript expression for the respective genes. Magic mRNAassay of renal cells is depicted. (K) Analysis comparing the percentage of cluster 8 and the interstitial fibrosis and tubular atrophy (IFTA) grade for each patient. Percentage of cluster 8 is calculated with respect to the PTEC number in each patient. P < 0.05 based on the Kruskal-Wallis test and Pearson correlation analysis. (L) UMAP showing time-resolved PTECs clustering after transplantation (shown as days after transplantation). Note the emergence of cluster 8 with time after transplantation. (M) Cluster-type-specific genes analysis revealed *CDH6* as being among the top two driver genes that underlie the dynamic activity in cluster 8. (N) Co-immunostaining showing that CDH6^pos cells displayed a tight intimate association with ACTA2^pos myofibroblasts within human kidney allograft, with CDH6^neg foci showing no ACTA2^pos myofibroblasts. (O) Immunoblot showing that subconfluent human primary PTECs activated SOX9, which waned upon confluency. (P and Q) Co-immunoanalysis (P) and qPCR (Q) showing reduction in CDH6^pos cells and *Cdh6* mRNA, respectively, upon removal of Sox9^on-on activity (blinded analysis, unpaired two-sided Student’s t test; data are shown as mean ± SEM). Scale bars in whole scanned image (P), 1000 μm; all others, 100 μm.

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Comment in

Switching off SOX9 for epithelial recovery after AKI.
Wang M. Wang M. Nat Rev Nephrol. 2024 May;20(5):271. doi: 10.1038/s41581-024-00830-4. Nat Rev Nephrol. 2024. PMID: 38532003 No abstract available.

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References

1. Rockey DC, Bell PD, Hill JA, Fibrosis—A common pathway to organ injury and failure. N. Engl. J. Med 372, 1138–1149 (2015). doi: 10.1056/NEJMra1300575; pmid: - DOI - PubMed
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[1] Rockey DC, Bell PD, Hill JA, Fibrosis—A common pathway to organ injury and failure. N. Engl. J. Med 372, 1138–1149 (2015). doi: 10.1056/NEJMra1300575; pmid: - DOI - PubMed

[2] Rockey DC, Bell PD, Hill JA, Fibrosis—A common pathway to organ injury and failure. N. Engl. J. Med 372, 1138–1149 (2015). doi: 10.1056/NEJMra1300575; pmid: - DOI - PubMed

[3] Henderson NC, Rieder F, Wynn TA, Fibrosis: From mechanisms to medicines. Nature 587, 555–566 (2020). doi: 10.1038/s41586-020-2938-9 - DOI - PMC - PubMed

[4] Henderson NC, Rieder F, Wynn TA, Fibrosis: From mechanisms to medicines. Nature 587, 555–566 (2020). doi: 10.1038/s41586-020-2938-9 - DOI - PMC - PubMed

[5] Konieczny P, Naik S, Healing without scarring. Science 372, 346–347 (2021). doi: 10.1126/science.abi5770 - DOI - PubMed

[6] Konieczny P, Naik S, Healing without scarring. Science 372, 346–347 (2021). doi: 10.1126/science.abi5770 - DOI - PubMed

[7] Kumar S, Cellular and molecular pathways of renal repair after acute kidney injury. Kidney Int 93, 27–40 (2018). doi: 10.1016/j.kint.2017.07.030; - DOI - PubMed

[8] Kumar S, Cellular and molecular pathways of renal repair after acute kidney injury. Kidney Int 93, 27–40 (2018). doi: 10.1016/j.kint.2017.07.030; - DOI - PubMed

[9] Liu J et al., Molecular characterization of the transition from acute to chronic kidney injury following ischemia/reperfusion. JCI Insight 2, e94716 (2017). doi: 10.1172/jci.insight.94716; - DOI - PMC - PubMed

[10] Liu J et al., Molecular characterization of the transition from acute to chronic kidney injury following ischemia/reperfusion. JCI Insight 2, e94716 (2017). doi: 10.1172/jci.insight.94716; - DOI - PMC - PubMed

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SOX9 switch links regeneration to fibrosis at the single-cell level in mammalian kidneys

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SOX9 switch links regeneration to fibrosis at the single-cell level in mammalian kidneys

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