A single cell atlas of human teeth

Teeth exert fundamental functions related to mastication and speech. Despite their great biomedical importance, an overall picture of their cellular and molecular composition is still missing. In this study, we have mapped the transcriptional landscape of the various cell populations that compose human teeth at single-cell resolution, and we analyzed in deeper detail their stem cell populations and their microenvironment. Our study identified great cellular heterogeneity in the dental pulp and the periodontium. Unexpectedly, we found that the molecular signatures of the stem cell populations were very similar, and that their distinctive behavior could be due to substantial differences between their microenvironments. Our findings suggest that the microenvironmental specificity is the potential source for the major functional differences of the stem cells located in the various tooth compartments and open new perspectives towards cell-based dental therapeutic approaches.

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Identification of Distinct Breast Cancer Stem Cell Populations Based on Single-Cell Analyses of Functionally Enriched Stem and Progenitor Pools

Stem Cell Reports ◽

10.1016/j.stemcr.2015.12.006 ◽

2016 ◽

Vol 6 (1) ◽

pp. 121-136 ◽

Cited By ~ 45

Author(s):

Nina Akrap ◽

Daniel Andersson ◽

Eva Bom ◽

Pernilla Gregersson ◽

Anders Ståhlberg ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cell ◽

Cancer Stem Cell ◽

Single Cell ◽

Breast Cancer Stem Cell ◽

Cell Populations ◽

Stem Cell Populations

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Chronic AMPK inactivation slows SHH medulloblastoma progression by inhibiting mTORC1 signaling and depleting tumor stem cell populations

10.1101/2021.12.09.471978 ◽

2021 ◽

Author(s):

Taylor Dismuke ◽

Daniel S Malawsky ◽

Hedi Liu ◽

Jay Brenman ◽

Andrey Tikunov ◽

...

Keyword(s):

Stem Cell ◽

Genetic Model ◽

Cellular Heterogeneity ◽

Tumor Stem Cell ◽

Cell Populations ◽

Therapeutic Effects ◽

Conditional Expression ◽

Mtorc1 Signaling ◽

Stem Cell Populations

We show that inactivating AMPK in vivo in a genetic model of medulloblastoma depletes tumor stem cell populations and slows tumor progression. Medulloblastoma, the most common malignant pediatric brain tumor, grows as heterogenous communities comprising diverse types of tumor and stromal cells. We have previously shown that different types of cells in medulloblastomas show different sensitivities to specific targeted therapies. To determine if specific populations depend on AMPK, we analyzed mice with AMPK-inactivated medulloblastomas. We engineered mice with brain-wide, conditional deletion of the AMPK catalytic subunits Prkaa1 and Prkaa2 and conditional expression SmoM2, an oncogenic Smo allele that hyperactivates Sonic Hedgehog (SHH) signaling. We compared the medulloblastomas that formed in these mice to tumors that form in AMPK-intact mice with conditional SmoM2 expression. AMPK-inactivated tumors progressed more slowly, allowing longer event-free survival. AMPK inactivation altered the cellular heterogeneity, determined by scRNA-seq, increasing differentiation, decreasing tumor stem cell populations and reducing glio-neuronal multipotency. Mechanistically, AMPK inactivation altered glycolytic gene expression and decreased mTORC1 pathway activation. Hk2-deletion reproduced key aspects of the AMPK-inactivation phenotype, implicating altered glycolysis in the tumor suppressive effect of AMPK inactivation. Our results show that AMPK inactivation impairs tumor growth through mechanisms that disproportionately affect tumor stem cell populations. As stem cells are intrinsically resistant to current cytotoxic therapy that drives recurrence, finding ways to target these populations may prevent treatment failure. Our data suggest that targeted AMPK inactivation may produce therapeutic effects in tumor stem cell populations refractory to other therapeutic approaches.

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Single Cell Analysis Demonstrates Significant Transcriptional Heterogeneity Within Tightly-Sorted Murine Hematopoietic Stem Cell Populations

Journal of Surgical Research ◽

10.1016/j.jss.2009.11.482 ◽

2010 ◽

Vol 158 (2) ◽

pp. 347

Author(s):

J.P. Glotzbach ◽

I.N. Vial ◽

M. Januszyk ◽

V.W. Wong ◽

H. Thangarajah ◽

...

Keyword(s):

Stem Cell ◽

Single Cell ◽

Hematopoietic Stem Cell ◽

Single Cell Analysis ◽

Cell Populations ◽

Cell Analysis ◽

Hematopoietic Stem ◽

Murine Hematopoietic Stem Cell ◽

Stem Cell Populations

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Combined Single-Cell Functional and Gene Expression Analysis Resolves Heterogeneity within Stem Cell Populations

Cell Stem Cell ◽

10.1016/j.stem.2015.04.004 ◽

2015 ◽

Vol 16 (6) ◽

pp. 712-724 ◽

Cited By ~ 248

Author(s):

Nicola K. Wilson ◽

David G. Kent ◽

Florian Buettner ◽

Mona Shehata ◽

Iain C. Macaulay ◽

...

Keyword(s):

Gene Expression ◽

Stem Cell ◽

Single Cell ◽

Expression Analysis ◽

Gene Expression Analysis ◽

Cell Populations ◽

Stem Cell Populations

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Single cell transcriptomics of human epidermis reveals basal stem cell transition states

10.1101/784579 ◽

2019 ◽

Cited By ~ 3

Author(s):

Shuxiong Wang ◽

Michael L. Drummond ◽

Christian F. Guerrero-Juarez ◽

Eric Tarapore ◽

Adam L. MacLean ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Single Cell ◽

Cell Communication ◽

Cell Populations ◽

Cell Heterogeneity ◽

Stable States ◽

Interfollicular Epidermis ◽

Epidermal Homeostasis ◽

Stem Cell Populations

ABSTRACTHow stem cells give rise to human interfollicular epidermis is unclear despite the crucial role the epidermis plays in barrier and appendage formation. Here we use single cell-RNA sequencing to interrogate basal stem cell heterogeneity of human interfollicular epidermis and find at least four spatially distinct stem cell populations that decorate the top and bottom of rete ridge architecture and hold transitional positions between the basal and suprabasal epidermal layers. Cell-cell communication modeling through co-variance of cognate ligand-receptor pairs indicate that the basal cell populations distinctly serve as critical signaling hubs that maintain epidermal communication. Combining pseudotime, RNA velocity, and cellular entropy analyses point to a hierarchical differentiation lineage supporting multi-stem cell interfollicular epidermal homeostasis models and suggest the “transitional” basal stem cells are stable states essential for proper stratification. Finally, alterations in differentially expressed “transitional” basal stem cell genes result in severe thinning of human skin equivalents, validating their essential role in epidermal homeostasis and reinforcing the critical nature of basal stem cell heterogeneity.

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Abstract 939: Single cell mRNA expression profiling reveals heterogeneity of normal and malignant breast stem cell populations

10.1158/1538-7445.am2017-939 ◽

2017 ◽

Author(s):

Shamileh Fouladdel ◽

Justin Colacino ◽

Ebrahim Azizi ◽

Max S. Wicha

Keyword(s):

Stem Cell ◽

Mrna Expression ◽

Single Cell ◽

Expression Profiling ◽

Cell Populations ◽

Breast Stem Cell ◽

Malignant Breast ◽

Stem Cell Populations ◽

Mrna Expression Profiling

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Unique epigenetic influence of H2AX phosphorylation and H3K56 acetylation on normal stem cell radioresponses

Molecular Biology of the Cell ◽

10.1091/mbc.e16-01-0017 ◽

2016 ◽

Vol 27 (8) ◽

pp. 1332-1345 ◽

Cited By ~ 16

Author(s):

Keith M. Jacobs ◽

Sandeep Misri ◽

Barbara Meyer ◽

Suyash Raj ◽

Cheri L. Zobel ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Ionizing Radiation ◽

Tissue Injury ◽

Cellular Heterogeneity ◽

Cell Populations ◽

Normal Stem Cell ◽

Dna Breaks ◽

Culture Models ◽

Stem Cell Populations

Normal tissue injury resulting from cancer radiotherapy is often associated with diminished regenerative capacity. We examined the relative radiosensitivity of normal stem cell populations compared with non–stem cells within several radiosensitive tissue niches and culture models. We found that these stem cells are highly radiosensitive, in contrast to their isogenic differentiated progeny. Of interest, they also exhibited a uniquely attenuated DNA damage response (DDR) and muted DNA repair. Whereas stem cells exhibit reduced ATM activation and ionizing radiation–induced foci, they display apoptotic pannuclear H2AX-S139 phosphorylation (γH2AX), indicating unique radioresponses. We also observed persistent phosphorylation of H2AX-Y142 along the DNA breaks in stem cells, which promotes apoptosis while inhibiting DDR signaling. In addition, down-regulation of constitutively elevated histone-3 lysine-56 acetylation (H3K56ac) in stem cells significantly decreased their radiosensitivity, restored DDR function, and increased survival, signifying its role as a key contributor to stem cell radiosensitivity. These results establish that unique epigenetic landscapes affect cellular heterogeneity in radiosensitivity and demonstrate the nonubiquitous nature of radiation responses. We thus elucidate novel epigenetic rheostats that promote ionizing radiation hypersensitivity in various normal stem cell populations, identifying potential molecular targets for pharmacological radioprotection of stem cells and hopefully improving the efficacy of future cancer treatment.

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