Single cell landscape of parietal epithelial cells in healthy and diseased states

The biology and diversity of glomerular parietal epithelial cells (PECs) are important for understanding podocyte regeneration and crescent formation. Although protein markers have revealed the morphological heterogeneity of PECs, the molecular characteristics of PEC subpopulations remain largely unknown. Here, we performed a comprehensive analysis of PECs using single-cell RNA sequencing (scRNA-seq) data. Our analysis identified five distinct PEC subpopulations: PEC-A1, PEC-A2, PEC-A3, PEC-A4 and PEC-B. Among these subpopulations, PEC- A1 and PEC-A2 were characterized as podocyte progenitors while PEC-A4 represented tubular progenitors. Further dynamic signaling network analysis indicated that activation of PEC-A4 and the proliferation of PEC-A3 played pivotal roles in crescent formation. Analyses suggested that upstream signals released by podocytes, immune cells, endothelial cells and mesangial cells serve as pathogenic signals and may be promising intervention targets in crescentic glomerulonephritis. Pharmacological blockade of two such pathogenic signaling targets, proteins Mif and Csf1r, reduced hyperplasia of the PECs and crescent formation in anti-glomerular basement membrane glomerulonephritis murine models. Thus, our study demonstrates that scRNA-seq-based analysis provided valuable insights into the pathology and therapeutic strategies for crescentic glomerulonephritis. The biology and diversity of glomerular parietal epithelial cells (PECs) are important for understanding podocyte regeneration and crescent formation. Although protein markers have revealed the morphological heterogeneity of PECs, the molecular characteristics of PEC subpopulations remain largely unknown. Here, we performed a comprehensive analysis of PECs using single-cell RNA sequencing (scRNA-seq) data. Our analysis identified five distinct PEC subpopulations: PEC-A1, PEC-A2, PEC-A3, PEC-A4 and PEC-B. Among these subpopulations, PEC- A1 and PEC-A2 were characterized as podocyte progenitors while PEC-A4 represented tubular progenitors. Further dynamic signaling network analysis indicated that activation of PEC-A4 and the proliferation of PEC-A3 played pivotal roles in crescent formation. Analyses suggested that upstream signals released by podocytes, immune cells, endothelial cells and mesangial cells serve as pathogenic signals and may be promising intervention targets in crescentic glomerulonephritis. Pharmacological blockade of two such pathogenic signaling targets, proteins Mif and Csf1r, reduced hyperplasia of the PECs and crescent formation in anti-glomerular basement membrane glomerulonephritis murine models. Thus, our study demonstrates that scRNA-seq-based analysis provided valuable insights into the pathology and therapeutic strategies for crescentic glomerulonephritis. Translational StatementWe used glomerular single-cell RNA-sequencing data to precisely define the cellular identities of glomerular parietal epithelial cells (PECs), improving our understanding of their heterogeneity and biology. Podocyte progenitors were characterized from PEC subsets, and the molecular mechanisms behind PEC activation and proliferation were revealed. We further validated our findings using targeted inhibitors in animal experiments. These mechanisms play a crucial role in the development of crescentic glomerulonephritis and could be potential targets for disease intervention. We used glomerular single-cell RNA-sequencing data to precisely define the cellular identities of glomerular parietal epithelial cells (PECs), improving our understanding of their heterogeneity and biology. Podocyte progenitors were characterized from PEC subsets, and the molecular mechanisms behind PEC activation and proliferation were revealed. We further validated our findings using targeted inhibitors in animal experiments. These mechanisms play a crucial role in the development of crescentic glomerulonephritis and could be potential targets for disease intervention. Anatomically, glomerular parietal epithelial cells (PECs) line the Bowman’s capsule and are considered to be a continuous cell pool between podocytes and tubular epithelial cells (TECs).1Shankland S.J. Smeets B. Pippin J.W. et al.The emergence of the glomerular parietal epithelial cell.Nat Rev Nephrol. 2014; 10: 158-173Crossref PubMed Scopus (122) Google Scholar PECs comprise heterogeneous cell populations, including peripolar cells or parietal podocytes located at the interface with podocytes, cuboidal PECs neighboring TECs, and widely distributed classic flat PECs.1Shankland S.J. Smeets B. Pippin J.W. et al.The emergence of the glomerular parietal epithelial cell.Nat Rev Nephrol. 2014; 10: 158-173Crossref PubMed Scopus (122) Google Scholar,2D'Agati V.D. Shankland S.J. Recognizing diversity in parietal epithelial cells.Kidney Int. 2019; 96: 16-19Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar The hierarchical transition states of podocyte progenitors and TEC progenitors within PECs have been described in adult humans. These progenitors are characterized by the coexpression of surface markers CD133 and CD24.3Ronconi E. Sagrinati C. Angelotti M.L. et al.Regeneration of glomerular podocytes by human renal progenitors.J Am Soc Nephrol. 2009; 20: 322-332Crossref PubMed Scopus (451) Google Scholar, 4Smeets B. Angelotti M.L. Rizzo P. et al.Renal progenitor cells contribute to hyperplastic lesions of podocytopathies and crescentic glomerulonephritis.J Am Soc Nephrol. 2009; 20: 2593-2603Crossref PubMed Scopus (166) Google Scholar, 5Angelotti M.L. Ronconi E. Ballerini L. et al.Characterization of renal progenitors committed toward tubular lineage and their regenerative potential in renal tubular injury.Stem Cells. 2012; 30: 1714-1725Crossref PubMed Scopus (257) Google Scholar During glomerulogenesis, PECs and podocytes derive from the same ancestral tissue (i.e., metanephric mesenchyme) and share a common phenotype until the S-shaped body stage.1Shankland S.J. Smeets B. Pippin J.W. et al.The emergence of the glomerular parietal epithelial cell.Nat Rev Nephrol. 2014; 10: 158-173Crossref PubMed Scopus (122) Google Scholar However, the regeneration of podocytes from PECs is controversial.6Moeller M.J. Tharaux P.L. Cellular regeneration of podocytes from parietal cells: the debate is still open.Kidney Int. 2019; 96: 542-544Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar A limited number of transitional cells located at the glomerular vascular stalk exhibit features of both PECs and podocytes. These parietal podocytes are recruited to the capillary tuft during development and disappear from the Bowman’s capsule with increasing age.7Appel D. Kershaw D.B. Smeets B. et al.Recruitment of podocytes from glomerular parietal epithelial cells.J Am Soc Nephrol. 2009; 20: 333-343Crossref PubMed Scopus (398) Google Scholar,8Berger K. Schulte K. Boor P. et al.The regenerative potential of parietal epithelial cells in adult mice.J Am Soc Nephrol. 2014; 25: 693-705Crossref PubMed Scopus (91) Google Scholar Studies have also found that a subpopulation of PECs replaces podocytes during aging or after podocyte depletion in adult mice.9Kaverina N.V. Eng D.G. Miner J.H. et al.Parietal epithelial cell differentiation to a podocyte fate in the aged mouse kidney.Aging (Albany NY). 2020; 12: 17601-17624Crossref PubMed Google Scholar,10Kaverina N.V. Eng D.G. Freedman B.S. et al.Dual lineage tracing shows that glomerular parietal epithelial cells can transdifferentiate toward the adult podocyte fate.Kidney Int. 2019; 96: 597-611Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar Crescent formation is characterized by hyperplasia of activated PECs that de novo express CD44. This plays a pivotal role in disease progression of focal segmental glomerular sclerosis and crescentic glomerulonephritis.11Kuppe C. Leuchtle K. Wagner A. et al.Novel parietal epithelial cell subpopulations contribute to focal segmental glomerulosclerosis and glomerular tip lesions.Kidney Int. 2019; 96: 80-93Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar, 12Eymael J. Sharma S. Loeven M.A. et al.CD44 is required for the pathogenesis of experimental crescentic glomerulonephritis and collapsing focal segmental glomerulosclerosis.Kidney Int. 2018; 93: 626-642Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar, 13Fatima H. Moeller M.J. Smeets B. et al.Parietal epithelial cell activation marker in early recurrence of FSGS in the transplant.Clin J Am Soc Nephrol. 2012; 7: 1852-1858Crossref PubMed Scopus (98) Google Scholar The PEC activation and crescent formation result from diverse upstream pathomechanisms, such as podocyte injury or depletion14Smeets B. Uhlig S. Fuss A. et al.Tracing the origin of glomerular extracapillary lesions from parietal epithelial cells.J Am Soc Nephrol. 2009; 20: 2604-2615Crossref PubMed Scopus (211) Google Scholar, 15Smeets B. Moeller M.J. Parietal epithelial cells and podocytes in glomerular diseases.Semin Nephrol. 2012; 32: 357-367Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 16Pace J.A. Bronstein R. Guo Y. et al.Podocyte-specific KLF4 is required to maintain parietal epithelial cell quiescence in the kidney.Sci Adv. 2021; 7eabg6600Crossref PubMed Scopus (11) Google Scholar or inflammatory cell infiltration,17Lan H.Y. Nikolic-Paterson D.J. Atkins R.C. Involvement of activated periglomerular leukocytes in the rupture of Bowman’s capsule and glomerular crescent progression in experimental glomerulonephritis.Lab Invest. 1992; 67: 743-751PubMed Google Scholar, 18Ophascharoensuk V. Pippin J.W. Gordon K.L. et al.Role of intrinsic renal cells versus infiltrating cells in glomerular crescent formation.Kidney Int. 1998; 54: 416-425Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar, 19Ryu M. Migliorini A. Miosge N. et al.Plasma leakage through glomerular basement membrane ruptures triggers the proliferation of parietal epithelial cells and crescent formation in non-inflammatory glomerular injury.J Pathol. 2012; 228: 482-494Crossref PubMed Scopus (63) Google Scholar A detailed description of how different subpopulations of PECs respond to pathogenic upstream signals is essential for identifying therapeutic targets for these complicated diseases. On the basis of mouse glomerular single-cell RNA-sequencing (scRNA-seq) data, we gained a profound understanding of PEC heterogeneity and focused on characterizing podocyte progenitors within the Bowman’s capsule. We also constructed a dynamic signaling network of PEC activation and proliferation in crescent formation and identified several potential therapeutic targets. Finally, we validated our analysis result in vivo using pharmacologic blockade of macrophage migration inhibitory factor (Mif) and colony-stimulating factor 1 receptor (Csf1r). These treatments reduced the hyperplasia of PECs and crescent formation in anti–glomerular basement membrane (GBM) glomerulonephritis mice. Anti-GBM glomerulonephritis in to as L. et of the cell and to injury.J Am Soc Nephrol. 2020; PubMed Scopus Google Y. A. R. et glomerulonephritis through activation of podocyte receptor Int. Full Text Full Text PDF PubMed Scopus Google Scholar after were with body of or as the were with of or were used as inhibitors of Mif and Csf1r, Y. Y. et with data of targeted PubMed Scopus Google S. et development of a of signaling Google Scholar and were for and were for were for M. N. H. et for of from J Pathol. Full Text Full Text PDF PubMed Scopus Google Scholar animal were and by the of and number glomerular data were from A of and were to the P.L. A. a for the of cell 2020; PubMed Scopus (38) Google Scholar, Y. S. E. et analysis of single-cell 2021; Full Text Full Text PDF PubMed Scopus Google Scholar, N. J. et and of single-cell data with 2019; PubMed Scopus Google Scholar, L. J. the analysis of data by of and and PubMed Scopus Google Scholar, Y. et single-cell PubMed Scopus Google Scholar, J. M. et al.The single-cell of 2019; PubMed Scopus Google Scholar, Y. et of Full Text Full Text PDF PubMed Scopus Google Scholar, R. A. et of 2018; PubMed Scopus Google Scholar, S. et single-cell network and PubMed Scopus Google Scholar, S. L. et and analysis of using 2021; 12: PubMed Scopus Google Scholar were from at of number and were to and The of data using the and distributed data are as the using A or analysis of used to data were distributed or were the data are as the and the to the using between were using the or considered of the are in the and PECs at single-cell mouse glomerular data were and L. et of the cell and to injury.J Am Soc Nephrol. 2020; PubMed Scopus Google S. L. et insights into the early of glomerular injury in using single-cell RNA Int. Full Text Full Text PDF PubMed Scopus Google N. M. A. et single-cell of the mouse Am Soc Nephrol. 2018; PubMed Scopus Google Scholar PECs, TECs, endothelial cells, mesangial cells, vascular cells, and immune cells were identified The of endothelial cells, mesangial cells, and podocytes in and were with cell analysis et of glomerular cell and from mice.J Am Soc Nephrol. 2021; 32: PubMed Scopus Google Scholar to were identified by and in states were by of PECs and were by the and validated by from the is a tubular cell of several tubular cell is a of parietal epithelial The number of PECs and mouse in provided a for analysis glomerular cell were identified in with endothelial and mesangial cells in a mouse of human L. et of the cell and to injury.J Am Soc Nephrol. 2020; PubMed Scopus Google D.B. and murine of Int. Full Text Full Text PDF PubMed Scopus Google Scholar and of and and of podocyte of RNA and analysis revealed the transition between podocytes, PECs, and the diversity within PECs, we PECs into subpopulations on the of their and and subpopulations were from and as PEC-A1, PEC-A2, PEC-A3, and PEC-A4 and and of and progenitor and podocyte and hierarchical of PECs The heterogeneity of PECs in the Bowman’s capsule with identified V.D. Shankland S.J. Recognizing diversity in parietal epithelial cells.Kidney Int. 2019; 96: 16-19Abstract Full Text Full Text PDF PubMed Scopus (8) Google C. Leuchtle K. Wagner A. et al.Novel parietal epithelial cell subpopulations contribute to focal segmental glomerulosclerosis and glomerular tip lesions.Kidney Int. 2019; 96: 80-93Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar and and flat PECs 1 and podocyte markers were used to the transitional PECs at glomerular vascular stalk and The hierarchical transition of PECs to podocytes from to and to in adult mouse and were in these transition cells in the mouse PECs from renal tubular to Bowman’s capsule were characterized by and in human and mouse and PECs located between C. Leuchtle K. Wagner A. et al.Novel parietal epithelial cell subpopulations contribute to focal segmental glomerulosclerosis and glomerular tip lesions.Kidney Int. 2019; 96: 80-93Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar were with protein or factor and have been as the marker of B. P. S. et RNA sequencing the mesangial and diversity of glomerular cell 2021; 12: PubMed Scopus Google A. K. 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Ronconi E. Ballerini L. et al.Characterization of renal progenitors committed toward tubular lineage and their regenerative potential in renal tubular injury.Stem Cells. 2012; 30: 1714-1725Crossref PubMed Scopus (257) Google Scholar a cellular we found that and podocytes in in and of podocyte progenitors in to and into podocytes. signals podocyte progenitors in are of have been to podocyte differentiation of PECs, such as S. Angelotti M.L. et blockade podocytes in by intrinsic Int. 2018; Full Text Full Text PDF PubMed Scopus Google Scholar that podocyte regeneration of PECs is limited with increasing podocyte progenitors is can podocytes after podocyte injury or M.J. Tharaux P.L. Cellular regeneration of podocytes from parietal cells: the debate is still open.Kidney Int. 2019; 96: 542-544Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar are in glomerular the of in and and podocytes in both that into podocytes in to PEC-A3 shows the transition to that cells are during crescent formation. A that PECs can into using lineage can be and the also the differentiation of hyperplastic PEC into R. et of progenitor cells into podocytes glomerulonephritis in PubMed Scopus Google Scholar However, podocytes from PECs as lineage tracing N.V. Eng D.G. 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