Lung Stem Cell Self-Renewal Relies on BMI1-Dependent Control of Expression at Imprinted Loci

Abstract

Summary Bmi1 is required for the self-renewal of stem cells in many tissues including the lung epithelial stem cells, Bronchioalveolar Stem Cells (BASCs). Imprinted genes, which exhibit expression from only the maternally- or paternally-inherited allele, are known to regulate developmental processes but their role in adult cells remains a fundamental question. Many imprinted genes were de-repressed in Bmi1 knockout mice, and knockdown of Cdkn1c (p57) and other imprinted genes partially rescued the self-renewal defect of Bmi1 mutant lung cells. Expression of p57 and other imprinted genes was required for lung cell self-renewal in culture and correlated with repair of lung epithelial cell injury in vivo. Our data suggest that Bmi1-dependent regulation of expressed alleles at imprinted loci, distinct from imprinting per se, is required for control of lung stem cells. We anticipate that the regulation and function of imprinted genes is crucial for self-renewal in diverse adult tissue-specific stem cells.

Monoallelic expression of TMPRSS2/ERG in prostate cancer stem cells

“…1b). As all fractions contained fusion-positive cells, this implied an allelic exclusion or imprint, as seen for other genes in embryonal tumours, the developing embryo and more recently in adult lung tissue SCs 21 . We now wished to test whether allelic restriction was driven by the fusion event, or was a property of TMPRSS2 in the hierarchical epithelial populations.…”

Stem Cells and Cell Therapies in Lung Biology and Diseases: Conference Report

“…Parallel studies, and the refinement of cell separative strategies used by other laboratories, have since shown that candidate stem/progenitor cells isolated from different regions along the proximodistal lung axis share a similar if not identical biomarker repertoire. These include bronchioalveolar stem cells (BASCs) (24), bronchiolar progenitor cells (25), and multipotent a6 pos b4 pos cells, recently shown to recapitulate lung morphogenesis in a sub-kidney capsule lung organoid transplant assay (26). Dr. Bertoncello argued that although this reductionist approach provides powerful tools to monitor the status of stem/ progenitor pools in the normal and diseased lung, and to identify regulatory factors, cytokines, and pathways that specify their fate, much still remains to be done to precisely understand what these assays are telling us about the organization, regulation, and regenerative potential of endogenous lung stem cells in situ.…”

“…To distinguish between these possibilities, it will be necessary to achieve BASC-specific genetic marking in vivo. Dr. Kim also described her identification of an important new role in adult cells for Bmi1in the repression of genes that are typically regulated by imprinting mechanisms (24). Expression of p57, Igf2, and other imprinted genes was higher in BASCs compared with AT2 cells, was required for wild-type lung stem cell self-renewal in culture, and correlated with the ability of stem cells to VERMONT STEM CELL CONFERENCE effectively repair damaged lung epithelium in vivo.…”

Therapeutic effect of lung mixed culture-derived epithelial cells on lung fibrosis

“…[10][11][12] In addition to these stem cells, many groups have reported that certain populations of putative stem/progenitor cells are resident in the mouse lung. [13][14][15][16] Bronchioalveolar stem cells (BASCs) characterized by coexpression of Clara cell secretory protein (CCSP/CC10) and surfactant protein (SP)-C have differentiating capacity to both airway and alveolar lineages, and contribute to alveolar epithelial homeostasis and repair after injury. 14,17 On the other hand, a lineage-tracing investigation suggested that CCSP-expressing cells including BASCs do not contribute to either the alveolar epithelial cell population during normal homeostasis or alveolar epithelial regeneration after naphthalene injury.…”

“…[13][14][15][16] Bronchioalveolar stem cells (BASCs) characterized by coexpression of Clara cell secretory protein (CCSP/CC10) and surfactant protein (SP)-C have differentiating capacity to both airway and alveolar lineages, and contribute to alveolar epithelial homeostasis and repair after injury. 14,17 On the other hand, a lineage-tracing investigation suggested that CCSP-expressing cells including BASCs do not contribute to either the alveolar epithelial cell population during normal homeostasis or alveolar epithelial regeneration after naphthalene injury. 13 However, another lineage-tracing investigation showed a striking increase of CCSP þ cells-derived AEC II and AEC I in BLM-induced fibrotic pulmonary lesions.…”