Final Report Summary - EXPAND (Defining the cellular dynamics leading to tissue expansion)
Stem cells (SCs) ensure the development of the different tissues during morphogenesis and tissue homeostasis during adult life. SCs are critical for regenerating tissue after injuries and they play a role in tumor initiation. The aim of this project is to investigate the cellular and molecular mechanisms that regulate tissue expansion and cell fate decision during mammalian development, mechanical tissue expansion and tissue repair. To achieve this, we use state-of-the-art genetic mouse models to analyze the proliferation dynamics and fate of individual SCs in their native microenvironment. We collaborate with physicists to develop mathematical model that describes the behavior of SCs in condition of tissue expansion (postnatal growth, tissue regeneration, forced mediated tissue expansion, tumor initiation). Defining the cellular and molecular mechanisms underlying tissue growth and expansion during development and how these mechanisms differ from tissue regeneration in adulthood have important implications for understanding developmental defects and for enhancing tissue regeneration.
In this project, we defined the clonal dynamics allowing tumor initiation, and showed that oncogene induces a strong increase in self-renewing division leading to tumor formation (Sanchez-Danés, Nature 2016). During postnatal growth, the generation of the excess of cells arise from a constant imbalance of self-renewing division coupled with an ever-decreasing rate of proliferation, leading to a linear growth of the tissue (Dekoninck et al. Cell 2020). We show that mechanical stretching of the skin induces tissue expansion by a transient bias in the renewal activity of epidermal stem cells, while a second subpopulation of basal progenitors remains committed to differentiation (Aragona et al. Nature 2020). In contrast, during wound healing, epidermal progenitors divide more rapidly, but conserve their homeostatic mode of division, leading to their rapid depletion, whereas rapid asymmetric division of SCs give rise to new progenitors that mediated cellular expansion required for tissue repair. Molecular profiling of cells isolated from different skin regions surrounding the wound edge identified molecular signatures associated with proliferation, differentiation and migration (Aragona et al. Nature communications 2017).
Using multicolour lineage tracing and statistical analysis, we demonstrate the existence of a developmental switch from multipotency to unipotency during embryonic mammary gland development. Molecular profiling and single cell RNA-seq revealed that embryonic multipotent progenitors express a hybrid basal and luminal signature (Wuidart et al. Nature Cell Biology 2018). During postnatal development, adult homeostasis, pregnancy and lactation, the different cells types of the mammary gland are maintained by distinct unipotent lineage restricted SC populations (Wuidart, Genes Dev 2016). In contrast, at the early step of prostate postnatal development, multipotent basal SCs are located throughout the epithelium, and are progressively restricted at the distal tip of the ducts, whereas, pubertal development is mediated by unipotent lineage-restricted SCs (Tika et al. Development 2019). Our results uncover the spatiotemporal regulation of the switch from multipotency to unipotency in glandular epithelia
We showed that oncogenic Pik3ca reactivates multipotency in basal and luminal unipotent SCs. This reactivation of multipotency sets the stage for future intratumoral heterogeneity at the earliest stage of tumor development (Van Keymeulen, Nature 2015). We found that ablation of luminal cells reactivated basal SC (BaSC) multipotency from multiple glandular epithelia. Single-cell RNA-seq revealed that BaSC activate a hybrid basal and luminal cell differentiation program, reminiscent of the genetic program that regulates multipotency during embryonic development. Altogether, our study demonstrates that heterotypic cell communication is essential to repress multipotency maintain lineage fidelity in glandular epithelial SCs (Centoze et al. Nature 2020).
In this project, we defined the clonal dynamics allowing tumor initiation, and showed that oncogene induces a strong increase in self-renewing division leading to tumor formation (Sanchez-Danés, Nature 2016). During postnatal growth, the generation of the excess of cells arise from a constant imbalance of self-renewing division coupled with an ever-decreasing rate of proliferation, leading to a linear growth of the tissue (Dekoninck et al. Cell 2020). We show that mechanical stretching of the skin induces tissue expansion by a transient bias in the renewal activity of epidermal stem cells, while a second subpopulation of basal progenitors remains committed to differentiation (Aragona et al. Nature 2020). In contrast, during wound healing, epidermal progenitors divide more rapidly, but conserve their homeostatic mode of division, leading to their rapid depletion, whereas rapid asymmetric division of SCs give rise to new progenitors that mediated cellular expansion required for tissue repair. Molecular profiling of cells isolated from different skin regions surrounding the wound edge identified molecular signatures associated with proliferation, differentiation and migration (Aragona et al. Nature communications 2017).
Using multicolour lineage tracing and statistical analysis, we demonstrate the existence of a developmental switch from multipotency to unipotency during embryonic mammary gland development. Molecular profiling and single cell RNA-seq revealed that embryonic multipotent progenitors express a hybrid basal and luminal signature (Wuidart et al. Nature Cell Biology 2018). During postnatal development, adult homeostasis, pregnancy and lactation, the different cells types of the mammary gland are maintained by distinct unipotent lineage restricted SC populations (Wuidart, Genes Dev 2016). In contrast, at the early step of prostate postnatal development, multipotent basal SCs are located throughout the epithelium, and are progressively restricted at the distal tip of the ducts, whereas, pubertal development is mediated by unipotent lineage-restricted SCs (Tika et al. Development 2019). Our results uncover the spatiotemporal regulation of the switch from multipotency to unipotency in glandular epithelia
We showed that oncogenic Pik3ca reactivates multipotency in basal and luminal unipotent SCs. This reactivation of multipotency sets the stage for future intratumoral heterogeneity at the earliest stage of tumor development (Van Keymeulen, Nature 2015). We found that ablation of luminal cells reactivated basal SC (BaSC) multipotency from multiple glandular epithelia. Single-cell RNA-seq revealed that BaSC activate a hybrid basal and luminal cell differentiation program, reminiscent of the genetic program that regulates multipotency during embryonic development. Altogether, our study demonstrates that heterotypic cell communication is essential to repress multipotency maintain lineage fidelity in glandular epithelial SCs (Centoze et al. Nature 2020).