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Characterization of the Development of the Mouse Cochlear Epithelium at the Single Cell Level

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Characterization of the Development of the Mouse Cochlear Epithelium at the Single Cell Level ARTICLE https://doi.org/10.1038/s41467-020-16113-y OPEN Characterization of the development of the mouse cochlear epithelium at the single cell level Likhitha Kolla1,6, Michael C. Kelly1,6, Zoe F. Mann 2, Alejandro Anaya-Rocha1, Kathryn Ellis1, Abigail Lemons1, Adam T. Palermo 3, Kathy S. So3, Joseph C. Mays 1, Joshua Orvis4, Joseph C. Burns3, Ronna Hertzano4,5, ✉ Elizabeth C. Driver 1 & Matthew W. Kelley 1 Mammalian hearing requires the development of the organ of Corti, a sensory epithelium 1234567890():,; comprising unique cell types. The limited number of each of these cell types, combined with their close proximity, has prevented characterization of individual cell types and/or their developmental progression. To examine cochlear development more closely, we tran- scriptionally profile approximately 30,000 isolated mouse cochlear cells collected at four developmental time points. Here we report on the analysis of those cells including the identification of both known and unknown cell types. Trajectory analysis for OHCs indicates four phases of gene expression while fate mapping of progenitor cells suggests that OHCs and their surrounding supporting cells arise from a distinct (lateral) progenitor pool. Tgfβr1 is identified as being expressed in lateral progenitor cells and a Tgfβr1 antagonist inhibits OHC development. These results provide insights regarding cochlear development and demon- strate the potential value and application of this data set. 1 Laboratory of Cochlear Development, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA. 2 Centre for Craniofacial and Regenerative Biology, King’s College London, London, UK. 3 Decibel Therapeutics, 1325 Boylston, Str., Suite 500, Boston, MA 02215, USA. 4 Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA. 5 Department of Otorhinolaryngology Head and Neck Surgery, Anatomy and Neurobiology, and Institute for Genome Sciences, University of Maryland School of Medicine, ✉ Baltimore, MD 21201, USA. 6These authors contributed equally: Likhitha Kolla, Michael C. Kelly. email: [email protected] NATURE COMMUNICATIONS | (2020) 11:2389 | https://doi.org/10.1038/s41467-020-16113-y | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-16113-y he organ of Corti (OC), located in the floor of the scala manipulations and molecular genetic experiments suggest that Tmedia of the cochlea, acts as the primary sensory trans- otocyst precursor cells proceed through several rounds of lineage ducer of sound in mammals. This structure comprises a restriction that progressively specify subsets of cells as prosensory highly diverse cellular mosaic that includes two different types of cells, and ultimately as either HCs or SCs (ref. 1). mechanosensory hair cells (HCs), and an undefined number of To examine the transcriptional changes that occur during the associated supporting cell (SC) types (Fig. 1a). All of these cells formation of the OC, we dissociate cochlear duct cells at four are believed to arise from a developmental equivalence group developmental time points and then capture individual cells for referred to as the prosensory domain1. The results of embryologic analysis using single-cell RNAseq. Results identify multiple a c IPC Medial Lateral 40 HeC DC3 CC/OSC OPC HC 20 DC1/2 KO4 KO1 ISC KO2 0 tSNE 2 Inner hair cells Deiters cells IdC Outer hair cells Hensen’s cells IPhC –20 Inner phalangeal/ Claudius/ OC90+ border cells outer sulcus KO3 Inner pillar cells cells –25 0 25 Outer pillar cells KO tSNE 1 b d Acbd7 Ccer2 Cib2 Pcp4 Pvalb 4 5 4 5 4 3 4 3 4 3 3 3 2 2 2 2 2 HC 1 1 1 1 1 0 0 0 0 0 Anxa5 Fabp7 Gjb2 Matn4 Prss23 5 5 5 4 4 4 4 4 3 3 3 3 3 2 2 2 2 2 IPhC 1 1 1 1 1 0 0 0 0 0 Cryab Emid1 Igfbpl1 Npy S100b 5 4 6 4 3 3 3 3 4 2 2 2 2 2 1 1 1 1 0 0 0 0 0 Fam159b Ppp1r2 S100b Serpine2 Sm agp 4 4 3 3 3 3 3 2 2 2 2 2 1 1 1 OPC 1 1 0 0 0 0 0 Hes5 Pdzk1ip1 Ppp1r2 S100a1 Serpine2 4 4 4 4 4 3 3 3 3 3 2 2 2 2 2 1 1 1 1 1 DC1/2 0 0 0 0 0 Hes5 Igfbpl1 Lfng Prss23 S100a1 4 4 3 3 4 3 3 3 2 2 2 2 2 DC3 1 1 1 1 1 0 0 0 0 0 Egfl6 Fam159b Fst Nupr1 Pm ch 3 4 3 4 4 2 3 3 3 2 2 2 2 HeC1 1 1 IPC 1 1 0 0 0 0 0 Apoe Bmp4 Fbln2 Fst Npnt 4 4 5 3 4 3 3 4 2 3 3 2 2 2 2 1 1 1 1 1 0 0 0 0 0 CC/OSC Dcn Ddost Pdia6 Rcn3 Sdf2l1 HC IS 4 5 4 DC3 IdC Log-transformed expression level IPhCOPC 4 4 3 KO4 3 3 3 KO1 KO2 KO3 3 2 CC/OSC 2 2 2 2 1 IPC 1 1 1 1 HeC Oc90 0 0 0 0 0 DC1/2 Cpxm2 Ctgf Fkbp9 Kazald1 Tectb 4 4 4 4 5 3 3 4 3 3 3 e 2 2 2 2 2 P1 KO cells only 1 1 1 1 1 KO20 KO1 0 0 0 0 M.KO Cst3 Gjb6 Net1 Tectb Tsen15 L.KO1 Id 5 20 C 4 5 L.KO2 3 3 4 IS 4 3 IS 3 M 3 2 2 L.KO3 .K 2 IdC O L.KO 2 2 1 1 1 2 3 1 1 1 0 KO3 0 0 0 0 0 Calb1 Crabp1 Epyc Itm2a Stmn2 tSNE 2 4 4 5 4 3 3 4 3 –20 3 3 2 2 2 2 2 CALB1 Phal 1 1 1 1 1 KO4 0 0 0 0 0 KO Igf1 Matn1 Meg3 Rgcc Tm4sf1 0 25 -25 4 4 4 3 4 tSNE 1 3 3 3 3 2 2 2 2 2 FABP7 Pou4f3 ISC 1 1 1 1 1 Otoa Calb1 Fabp7 0 0 0 0 0 KO Cndp2 Oc90 Rnase1 Ttr Vmo1 5 6 4 6 5 5 3 4 4 4 4 3 3 3 2 2 2 2 2 FABP7 1 1 1 1 OC90+ 0 0 0 0 0 Cdkn1c Fxyd6 Otoa Ptgds Smoc2 tSNE 2 6 4 4 4 4 4 3 3 3 3 2 2 2 2 IdC 2 1 1 1 1 0 0 0 0 0 tSNE 1 2 NATURE COMMUNICATIONS | (2020) 11:2389 | https://doi.org/10.1038/s41467-020-16113-y | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-16113-y ARTICLE Fig. 1 Characterization of cell types in the P1 cochlea. a Line drawing of a cross section of the floor of the cochlear duct at P1. Distinct cell types within the organ of Corti (OC) are color coded. b Heat map for ~14,000 cochlear cells collected from four separate experiments at P1. Top 25 differentially expressed (DE) genes for the 15 identified clusters are shown. Cellular identity for each cluster is indicated by a color bar at the top of the heat map, which corresponds to the legend in a, and by a cell name at the bottom. c tSNE plot for the same cells as in b. Cluster identities are indicated. d Violin plots showing normalized log-transformed expression values for the top five DE genes for each cell type (color coded as in c) by comparison with all other P1 cells (gray on the right in each graph). Bars indicate median expression level. e Upper left panel, tSNE plot of cells determined to be derived from KO (between the OC and medial edge of the cochlear duct). Lower left panel, feature plot for the same cells as in the upper panel indicating high expression of Otoa, Calb1, and Fabp7 (based on color) in different clusters of cells. Lower right panel, cross sections through the cochlear duct at P1, illustrating expression of CALB1 in the medial region of KO and FABP7 directly adjacent to the OC (arrow; scale bars, 20 μm). Lowest panel shows high-magnification view of expression of FABP7 (arrow, gray scale) at the lateral KO border (green line; scale bar, 10 μm). Upper right panel, summary diagram of the spatial distribution of KO cell clusters at P1. HC hair cells, IPhC inner phalangeal cells/border cells, IPC inner pillar cells, OPC outer pillar cells, DC1/2 Deiters’ cells rows 1 and 2, DC3, Deiters’ cells row 3, HeC Hensen’s cells, CC/OSC Claudius cells/outer sulcus cells, IdC interdental cells, ISC inner sulcus cells, KO Kölliker’s organ cells, L.KO lateral Kölliker’s organ cells, M.KO medial Kölliker’s organ cells, OC90 OC90+ cells. unique cell types at each time point, including both known types, during cochlear development. In particular, cells within KO play such as HCs and SCs, and previously unknown cell types, such as a role in the development of the tectorial membrane11, the gen- multiple unique cell types in Kölliker’s organ (KO). Cells col- eration of spontaneous activity required for maturation of spiral lected from E14 and E16 cochleae include prosensory cells; ganglion neurons12 and some cells within this region retain however, unbiased clustering indicates two distinct populations. prosensory potential13–15. However, since KO cells are morpho- Fate mapping of one of these populations demonstrates a strong logically homogenous, the extent of transcriptional heterogeneity bias toward lateral fates (OHCs and surrounding support cells), was unclear.
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