Defining epithelial cell dynamics and lineage relationships in the developing lacrimal gland

Abstract

The tear-producing lacrimal gland is a tubular organ that protects and lubricates the ocular surface. The lacrimal gland possesses many features that make it an excellent model in which to investigate tubulogenesis, but the cell types and lineage relationships that drive lacrimal gland formation are unclear. Using single-cell sequencing and other molecular tools, we reveal novel cell identities and epithelial lineage dynamics that underlie lacrimal gland development. We show that the lacrimal gland from its earliest developmental stages is composed of multiple subpopulations of immune, epithelial and mesenchymal cell lineages. The epithelial lineage exhibits the most substantial cellular changes, transitioning through a series of unique transcriptional states to become terminally differentiated acinar, ductal and myoepithelial cells. Furthermore, lineage tracing in postnatal and adult glands provides the first direct evidence of unipotent KRT5 + epithelial cells in the lacrimal gland. Finally, we show conservation of developmental markers between the developing mouse and human lacrimal gland, supporting the use of mice to understand human development. Together, our data reveal crucial features of lacrimal gland development that have broad implications for understanding epithelial organogenesis.

Salivary gland stem cells: A review of development, regeneration and cancer

“…In support of this segregation, an inverse expression profile to Krt14 was apparent for Kit expression following RA inhibition, where BMS 493 reduces expression of Kit in isolated epithelia explants (Abashev et al , 2017). In addition, KRT14 but not KIT is expressed by emerging SMA+ myoepithelial cells, which in the lacrimal gland give rise only to themselves (Farmer et al , 2017). …”

“…Genetic lineage tracing has also identified the transcription factor SOX2, an essential regulator of pluripotency of embryonic stem cells (ESCs), as a marker of progenitor cells for the duct and acinar lineages in the developing SMG and SLG (PG not investigated [Emmerson et al, 2017]), as well as many other epithelial tissues (Arnold et al, 2011). We recently reported that despite SOX2 being expressed throughout the oral epithelium, SOX2 has an essential role in the generation of acini:…”

“…genetic ablation of epithelial Sox2 prior to gland ontogenesis impairs the production of SOX101 acini but not ducts, in part, through cell death (Emmerson et al, 2017). This lineage specificity was postulated to be mediated by direct regulation of Sox10, a known regulator of acinar cell differentiation in the lacrimal glands .…”

“…Since SOX2 is regulated by acetylcholine derived from autonomic nerves innervating the developing and adult salivary gland Emmerson et al, 2017), it would be of therapeutic interest to know if innervation and neuronal signaling also regulates SOX2 expression in salivary cancer. To date no studies have investigated the correlation between SOX2, innervation of salivary gland tumors and cancer progression.…”

Identification of differentially expressed genes by single‐cell transcriptional profiling of umbilical cord and synovial fluid mesenchymal stem cells

“…Based on PCA and t-SNE analyses, we identified 11 subsets within hUC-MSCs and seven subsets within hSF-MSCs. Gene set enrichment analysis determined that there were 533, 57,32, 44,10, 319, 731, 1037, 90,25 and 230 differentially expressed genes (DEGs) in the 11 subsets of hUC- MSCs and 204, 577,30, 577,16, 57 and 35 DEGs in the seven subsets of hSF-MSCs. scRNA-seq was not only able to identify subpopulations of hUC-MSCs and hSF-MSCs within the sample sets, but also provided a digital transcript count of hUC-MSCs and hSF-MSCs within a single patient.…”