Biomolecules, Vol. 13, Pages 47: Application of Single-Cell RNA Sequencing in Ovarian Development

Figure 1. scRNA-seq technology identifies distinct cell subsets in the ovary of human, nonhuman primate, and mouse. The inner ovarian cortex of an adult human, the ovary of an adult human, human embryo, cynomolgus monkey, fetal mouse, and mouse embryo are collected. Then, the tissue is dissected to prepare a single-cell suspension, and cell subpopulations are identified based on the transcriptome data and specifically expressed genes. The ovary mainly contains six cell types, including oocytes, GCs, SCs, SMCs, ECs, and immune cells. The current scRNA-seq research has not found SMCs in the ovary of fetal mice ranging from 16.5 days postcoitum–PD3 or in those of human embryos between 5 and 26 weeks postfertilization. GCs, granulosa cells; SCs, stromal cells; SMCs, smooth muscle cells; ECs, endothelial cells.

Figure 1. scRNA-seq technology identifies distinct cell subsets in the ovary of human, nonhuman primate, and mouse. The inner ovarian cortex of an adult human, the ovary of an adult human, human embryo, cynomolgus monkey, fetal mouse, and mouse embryo are collected. Then, the tissue is dissected to prepare a single-cell suspension, and cell subpopulations are identified based on the transcriptome data and specifically expressed genes. The ovary mainly contains six cell types, including oocytes, GCs, SCs, SMCs, ECs, and immune cells. The current scRNA-seq research has not found SMCs in the ovary of fetal mice ranging from 16.5 days postcoitum–PD3 or in those of human embryos between 5 and 26 weeks postfertilization. GCs, granulosa cells; SCs, stromal cells; SMCs, smooth muscle cells; ECs, endothelial cells.

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Figure 2. Schematic diagram of the origin and development of pregranulosa cells. BPG cells originate from bipotential precursors, which are derived from ovarian epithelial progenitor cells. BPG cells enclose several primordial germ cells to form germ cell nests. Next, the nest breaks down, and BPG cells differentiate into granulosa cells of wave 1 follicles, which began to develop immediately after birth in the medullar region. Additionally, some BPGs may remain in the cortex for some time. With the development of the embryo, cortical BPG cells are replaced by EPG cells, which do not significantly reside in the ovarian medulla. EPG cells are derived from ovarian epithelial progenitor cells and become the granulosa cells of wave 2 follicles in the ovarian cortex, which represent the ovarian reserve (BPG, bipotential pregranulosa; EPG, epithelial pregranulosa).

Figure 2. Schematic diagram of the origin and development of pregranulosa cells. BPG cells originate from bipotential precursors, which are derived from ovarian epithelial progenitor cells. BPG cells enclose several primordial germ cells to form germ cell nests. Next, the nest breaks down, and BPG cells differentiate into granulosa cells of wave 1 follicles, which began to develop immediately after birth in the medullar region. Additionally, some BPGs may remain in the cortex for some time. With the development of the embryo, cortical BPG cells are replaced by EPG cells, which do not significantly reside in the ovarian medulla. EPG cells are derived from ovarian epithelial progenitor cells and become the granulosa cells of wave 2 follicles in the ovarian cortex, which represent the ovarian reserve (BPG, bipotential pregranulosa; EPG, epithelial pregranulosa).

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Figure 3. Canonical intercellular interactions in the ovary. (A) Schematic diagram showing the interaction of female human fetal germ cells and gonadal somatic cells mediated by typical signaling pathways. For the NOTCH signaling pathway, DLL3 and JAG1 is expressed on fetal germ cells, and the NOTCH receptor (NOTCH2) as well as targets (HES1) are expressed on somatic cells; for the TGF-β signaling pathway, BMP2 is expressed on somatic cells, and its receptor (BMPR1B) and target genes are expressed on fetal germ cells; for the KIT signaling pathway, the ligand KITL is expressed on somatic cells, while the KIT receptor is expressed on fetal germ cells. (B) Schematic illustration displaying the bidirectional communication between oocytes and granulosa cells during the primordial follicular assembly. For the NOTCH signaling pathway, the ligands DLL3, JAG1, and JAG2 are expressed on oocytes, and NOTCH receptors (NOTCH2) as well as targets (HES1 and RBPJ) are expressed on granulosa cells; for the TGF-β signaling pathway, GDF9 is expressed on oocytes, while its receptors (BMPR1A and BMPR2) and targets (ID1, ID2, and ID3) are expressed on oocytes and granulosa cells; for the KIT signaling pathway, the ligand KITL is expressed on granulosa cells, while the receptor KIT is expressed on oocytes; for gap junctions, GJA1 is expressed on granulosa cells, and GJC1 is expressed on oocytes. (C) Schematic diagram showing the characteristics of the intercellular crosstalk between oocytes and granulosa cells throughout folliculogenesis. For the NOTCH signaling pathway, the ligands DLL3 and JAG2 are expressed on oocytes, and NOTCH receptors (NOTCH2 and NOTCH3) as well as targets (HES1) are expressed on granulosa cells; for the TGF-β signaling pathway, GDF9 and BMP15 are expressed on oocytes, and its receptor (BMPR2) and targets (ID3) are expressed on oocytes and granulosa cells; for the KIT signaling pathway, the KITLG ligand is expressed on granulosa cells, while the KIT receptor is expressed on oocytes; for gap junctions, GJA1 and GJA5 are expressed on granulosa cells, and GJC1 and GJA3 are expressed on oocytes.

Figure 3. Canonical intercellular interactions in the ovary. (A) Schematic diagram showing the interaction of female human fetal germ cells and gonadal somatic cells mediated by typical signaling pathways. For the NOTCH signaling pathway, DLL3 and JAG1 is expressed on fetal germ cells, and the NOTCH receptor (NOTCH2) as well as targets (HES1) are expressed on somatic cells; for the TGF-β signaling pathway, BMP2 is expressed on somatic cells, and its receptor (BMPR1B) and target genes are expressed on fetal germ cells; for the KIT signaling pathway, the ligand KITL is expressed on somatic cells, while the KIT receptor is expressed on fetal germ cells. (B) Schematic illustration displaying the bidirectional communication between oocytes and granulosa cells during the primordial follicular assembly. For the NOTCH signaling pathway, the ligands DLL3, JAG1, and JAG2 are expressed on oocytes, and NOTCH receptors (NOTCH2) as well as targets (HES1 and RBPJ) are expressed on granulosa cells; for the TGF-β signaling pathway, GDF9 is expressed on oocytes, while its receptors (BMPR1A and BMPR2) and targets (ID1, ID2, and ID3) are expressed on oocytes and granulosa cells; for the KIT signaling pathway, the ligand KITL is expressed on granulosa cells, while the receptor KIT is expressed on oocytes; for gap junctions, GJA1 is expressed on granulosa cells, and GJC1 is expressed on oocytes. (C) Schematic diagram showing the characteristics of the intercellular crosstalk between oocytes and granulosa cells throughout folliculogenesis. For the NOTCH signaling pathway, the ligands DLL3 and JAG2 are expressed on oocytes, and NOTCH receptors (NOTCH2 and NOTCH3) as well as targets (HES1) are expressed on granulosa cells; for the TGF-β signaling pathway, GDF9 and BMP15 are expressed on oocytes, and its receptor (BMPR2) and targets (ID3) are expressed on oocytes and granulosa cells; for the KIT signaling pathway, the KITLG ligand is expressed on granulosa cells, while the KIT receptor is expressed on oocytes; for gap junctions, GJA1 and GJA5 are expressed on granulosa cells, and GJC1 and GJA3 are expressed on oocytes.

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Table 1. Possible marker genes of ovarian cells in different species demonstrated by single-cell RNA sequencing.

Table 1. Possible marker genes of ovarian cells in different species demonstrated by single-cell RNA sequencing.

Cell TypeMarker GenesSpeciesTechnologyReferenceFetal germ cells (FGCs)FGCsDDX4, DAZL, POU5F1, PRDM1, TFAP2C, KIT, NANOG, SALL4, LIN28A, LEFTY1, LEFTY2Mouse10XGenomics[47]DDX4, DAZLMouse10XGenomics[48]Mitotic FGCsPOU5F1, NANOGHumanSmart-seq2[39]Retinoid-acid-signaling-responsive FGCsSTRA8, ZGLP1, ANHX, ASB9, THRA/BTRHumanSmart-seq2[39]Meiotic prophase FGCsIl13RA2HumanSmart-seq2[39]Oogenesis stage FGCsPECAM1, ZP3, OOSP2HumanSmart-seq2[39]OocyteGDF9, ZP3, FIGLA, OOSP2Human10XGenomics[34]DDX4, ZP2, SYCP3, SOX30, ZAR1, DAZLHumanTang method[49]DDX4, ZP2, FIGLA, SOX30HumanSmart-seq2[50]GDF9, DDX4, SYCP3, ZP3, LMOD3, RBM46 NET01MonkeySTRT-seq[45]DDX4, DAZLMouse10XGenomics[36,38]DAZLMouse10XGenomics[37]Pregranulosa cellsFOXL2, WNT4, WNT6, KITLMouse10XGenomics[48]Granulosa cells (GCs) FOXL2, WT1HumanSmart-seq2[39]FOXL2, AMHHuman10XGenomics[34]AMH, CYP11A1, STAR, INHBAHuman10XGenomics[49]FOXL2, CDH2, GJA1, TNNI3HumanSmart-seq2[50]AMH, HSD17B1, SERPINE2, GSTA1Human10XGenomics[35]AMH, WT1, INH4MonkeySTRT-seq[45]AMHR2, KITLMouse10XGenomics[36,38]AMHR2Mouse10XGenomics[37]AMH, AMHR2, KITL, CYP19A1, FSHRMouse10XGenomics[51]Cumulus GCsIGFBP2, INHBB, IHHHumanSmart-seq2[50]IGFBP2, INHBB, IHH, VCAN, FST, HTRA1Human10XGenomics[35]HAS2, NPR2Mouse10XGenomics[51]Mural GCsKRT18, AKIRIN1, CYP19A1,HumanSmart-seq2[50]KRT18, AKIRIN1, LIHP, CITED2Human10XGenomics[35]FSHR, BMPR2, NPPCMouse10XGenomics[51]Stromal cellsDCN, COLLA1, COL6A1, PDGFRAHuman10XGenomics[34]DCN, COLLA1, COL3A1, APOEHumanSmart-seq2[50]DCN, LUMHuman10XGenomics[35]TCF21, COLLA2MonkeySTRT-seq[45]MFAP4, NR2F2Mouse10XGenomics[38]TCF21, NR2F2Mouse10XGenomics[36]MFAP4Mouse10XGenomics[37]Smooth muscle cellsTAGLN, RGS5, MYH11, MCAM, RERGlHuman10XGenomics[34]TAGLN, RGS5Human10XGenomics, Smart-seq2[35,50]DES, ACTA2MonkeySTRT-seq[45]Endothelial cellsCDH5 (CD144), PECAM1 (CD31)HumanSmart-seq2[39]vWF, CDH5Human10XGenomics[34]vWF, CD34 Human10XGenomics[50]vWF, CLDN5Human10XGenomics[35]vWF, CDH5MonkeySTRT-seq[45]APLNR, EGFL7Mouse10XGenomics[38]APLNRMouse10XGenomics[36,37]Immune cellsImmune cellsCD69, ITGB2Human10XGenomics[34]CD53, CXCR4Human10XGenomics[35]ELNE, MPOMouse10XGenomics[38]TYROBPMouse10XGenomics[36,37]Innate immune cellsCD68, IFI30Human10XGenomics[35]NK cellsCD3d, KLRB1MonkeySTRT-seq[45] Macrophages CD68, CD14MonkeySTRT-seq[45]Antigen-presenting cellsCD14, HLA-DRA, B2M, HLA-DQB1Human10XGenomics[34]T lymphocytesCD2, CD3G, CD8AHuman10XGenomics[34]T lymphocytesAW112010, CD3GMouse10XGenomics[51]B lymphocytesIGHM, CD37Mouse10XGenomics[51]Monocytes or monocyte-derived cellsCD14Mouse10XGenomics[51]

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