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Heterotypic cell-cell communication regulates glandular stem cell multipotency.

ABSTRACT: Glandular epithelia, including the mammary and prostate glands, are composed of basal cells (BCs) and luminal cells (LCs)^1,2. Many glandular epithelia develop from multipotent basal stem cells (BSCs) that are replaced in adult life by distinct pools of unipotent stem cells^1,3-8. However, adult unipotent BSCs can reactivate multipotency under regenerative conditions and upon oncogene expression^3,9-13. This suggests that an active mechanism restricts BSC multipotency under normal physiological conditions, although the nature of this mechanism is unknown. Here we show that the ablation of LCs reactivates the multipotency of BSCs from multiple epithelia both in vivo in mice and in vitro in organoids. Bulk and single-cell RNA sequencing revealed that, after LC ablation, BSCs activate a hybrid basal and luminal cell differentiation program before giving rise to LCs-reminiscent of the genetic program that regulates multipotency during embryonic development⁷. By predicting ligand-receptor pairs from single-cell data¹⁴, we find that TNF-which is secreted by LCs-restricts BC multipotency under normal physiological conditions. By contrast, the Notch, Wnt and EGFR pathways were activated in BSCs and their progeny after LC ablation; blocking these pathways, or stimulating the TNF pathway, inhibited regeneration-induced BC multipotency. Our study demonstrates that heterotypic communication between LCs and BCs is essential to maintain lineage fidelity in glandular epithelial stem cells.

SUBMITTER: Centonze A

PROVIDER: S-EPMC7116172 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Heterotypic cell-cell communication regulates glandular stem cell multipotency.

Centonze Alessia A Lin Shuheng S Tika Elisavet E Sifrim Alejandro A Fioramonti Marco M Malfait Milan M Song Yura Y Wuidart Aline A Van Herck Jens J Dannau Anne A Bouvencourt Gaelle G Dubois Christine C Dedoncker Nina N Sahay Amar A de Maertelaer Viviane V Siebel Christian W CW Van Keymeulen Alexandra A Voet Thierry T Blanpain Cédric C

Nature 20200826 7822

Glandular epithelia, including the mammary and prostate glands, are composed of basal cells (BCs) and luminal cells (LCs)1,2. Many glandular epithelia develop from multipotent basal stem cells (BSCs) that are replaced in adult life by distinct pools of unipotent stem cells1,3-8. However, adult unipotent BSCs can reactivate multipotency under regenerative conditions and upon oncogene expression3,9-13. This suggests that an active mechanism restricts BSC multipoten ...[more]

PMID: 32848220

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Project description:Glandular epithelia including the mammary gland (MG) and the prostate are composed of basal cells (BC) and luminal cells (LC). Lineage tracing demonstrates that many glandular epithelia initially develop from multipotent basal stem cells (BaSCs) that are replaced in adult life by distinct pool of unipotent stem cells (SCs). However, adult unipotent BaSC can reactivate multipotency and give rise to LCs upon transplantation or oncogene expression, demonstrating the important plasticity of BaSCs in regenerative and pathological conditions, and suggesting that an active mechanism restricts multipotency in BaSCs during physiological conditions. The nature of this mechanism is currently unknown. Here, we assess whether basal and luminal cell-cell communication restricts multipotency in glandular epithelia. To this end, we performed lineage tracing of BCs together with the ablation of LCs in different adult glandular epithelia including MG, prostate, sweat glands and salivary glands and assessed the fate of BaSCs overtime. Interestingly, ablation of LCs reactivated multipotency in unipotent adult BaSCs from multiple epithelia. To understand the molecular mechanisms that controls multipotency in adult BaSCs, we performed population bulk-RNA-seq and single cell RNA-seq of FACS isolated adult mammary epithelial cells after LC ablation. Upon LC ablation, adult BCs activate a hybrid basal and luminal differentiation program before giving rise to LC, reminiscent of the genetic program that regulate multipotency during embryonic development. Different signaling pathways including Notch, Wnt and Egfr were activated in BaSC and their progeny following LC ablation and blocking these pathways inhibited adult BC multipotency. Altogether, our study demonstrates that heterotypic LC and BC communication is essential to maintain lineage fidelity in glandular epithelial SC during homeostasis and uncovers the lineage trajectory and signaling pathways that promote multipotency during tissue repair.

Project description:BackgroundIn a number of disease processes, the body is unable to repair injured tissue, promoting the need to develop strategies for tissue repair and regeneration, including the use of cellular therapeutics. Trophoblast stem cells (TSCs) are considered putative stem cells as they differentiate into other subtypes of trophoblast cells. To identify cells for future therapeutic strategies, we investigated whether TSCs have properties of stem/progenitor cells including self-renewal and the capacity to differentiate into parenchymal cells of fetal organs, in vitro and in vivo.MethodsTSCs were isolated using anti-CD117 micro-beads, from embryonic day 18.5 placentas. In vitro, CD117+ TSCs were cultured, at a limiting dilution in growth medium for the development of multicellular clones and in specialized medium for differentiation into lung epithelial cells, cardiomyocytes, and retinal photoreceptor cells. CD117+ TSCs were also injected in utero into lung, heart, and the sub-retinal space of embryonic day 13.5 fetuses, and the organs were harvested for histological assessment after a natural delivery.ResultsWe first identified CD117+ cells within the labyrinth zone and chorionic basal plate of murine placentas in late pregnancy, embryonic day 18.5. CD117+ TSCs formed multicellular clones that remained positive for CD117 in vitro, consistent with self-renewal properties. The clonal cells demonstrated multipotency, capable of differentiating into lung epithelial cells (endoderm), cardiomyocytes (mesoderm), and retinal photoreceptor cells (ectoderm). Finally, injection of CD117+ TSCs in utero into lungs, hearts, and the sub-retinal spaces of fetuses resulted in their engraftment on day 1 after birth, and the CD117+ TSCs differentiated into lung alveolar epithelial cells, heart cardiomyocytes, and retina photoreceptor cells, corresponding with the organs in which they were injected.ConclusionsOur findings demonstrate that CD117+ TSCs have the properties of stem cells including clonogenicity, self-renewal, and multipotency. In utero administration of CD117+ TSCs engraft and differentiate into resident cells of the lung, heart, and retina during mouse development.

Project description:Adipose-derived stromal/stem cells (ASCs) are a promising cell source for vascular-based approaches to clinical therapeutics, as they have been shown to give rise to both endothelial and perivascular cells. While it is well known that ASCs can present a heterogeneous phenotypic profile, spontaneous interactions among these subpopulations that result in the formation of complex tissue structures have not been rigorously demonstrated. Our study reports the novel finding that ASCs grown in monolayers in the presence of angiogenic cues are capable of self-assembling into complex, three-dimensional vascular structures. This phenomenon is only apparent when the ASCs are seeded at a high density (20,000 cells/cm(2)) and occur through orchestrated interactions among three distinct subpopulations: CD31-positive cells (CD31+), ?-smooth muscle actin-positive cells (?SMA+), and cells that are unstained for both these markers (CD31-/?SMA-). Investigations into the kinetics of the process revealed that endothelial vessel-like structures initially arose from individual CD31+ cells through proliferation and their interactions with CD31-/?SMA- cells. During this period, ?SMA+ cells proliferated and appeared to migrate toward the vessel structures, eventually engaging in cell-cell contact with them after 1 week. By 2 weeks, the lumen-containing CD31+ vessels grew greater than a millimeter in length, were lined with vascular basement membrane proteins, and were encased within a dense, three-dimensional cluster of ?SMA+ and CD31-/?SMA- cells. The recruitment of ?SMA+ cells was largely due to platelet-derived growth factor (PDGF) signaling, as the inhibition of PDGF receptors substantially reduced ?SMA+ cell growth and vessel coverage. Additionally, we found that while hypoxia increased endothelial gene expression and vessel width, it also inhibited the growth of the ?SMA+ population. Together, these findings underscore the potential use of ASCs in forming mature vessels in vitro as well as the need for a further understanding of the heterotypic interactions among ASC subpopulations.

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Heterotypic cell-cell communication regulates glandular stem cell multipotency.

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Heterotypic cell-cell communication regulates glandular stem cell multipotency.

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