A multi-stem cell basis for craniosynostosis and calvarial mineralization

2021 ◽  
Author(s):  
Matthew Greenblatt ◽  
Seoyeon Bok ◽  
Alisha Yallowitz ◽  
Jason McCormick ◽  
Michelle Cung ◽  
...  
Keyword(s):  
Stem Cell ◽  
Endochondral Ossification ◽  
Distinct Form ◽  
Therapeutic Approaches ◽  
Genetic Ablation ◽  
Cell Lineages ◽  
Specific Fraction ◽  
Maladaptive Response ◽  
Suture Fusion ◽  
Stem Cell Populations

Abstract Craniosynostosis is a group of disorders of premature calvarial sutural fusion. An incomplete understanding of the calvarial stem cells (CSCs) that produce fusion-driving osteoblasts has limited the development of non-surgical therapeutic approaches for craniosynostosis. Here we show that both physiologic calvarial mineralization and pathologic calvarial fusion in craniosynostosis reflect the interaction of two separate stem cell lineages; a recently reported CathepsinK (CTSK) lineage CSC (CTSK+ CSC)1 and a separate Discoidin domain-containing receptor 2 (DDR2) lineage stem cell (DDR2+ CSC) identified in this study. Deletion of Twist1, a gene associated with human craniosynostosis2,3, solely in CTSK+ CSCs is sufficient to drive craniosynostosis, however the sites destined to fuse surprisingly display a marked depletion of CTSK+ CSCs and a corresponding expansion of DDR2+ CSCs. This DDR2+ CSC expansion is a direct maladaptive response to CTSK+ CSC depletion, as partial suture fusion occurred after genetic ablation of CTSK+ CSCs. This DDR2+ CSC is a specific fraction of DDR2+ lineage cells that displayed full stemness features, establishing the presence of two distinct stem cell lineages in the sutures, with each population contributing to physiologic calvarial mineralization. DDR2+ CSCs mediate a distinct form of endochondral ossification where an initial cartilage template is formed but the recruitment of hematopoietic marrow is absent. Direct implantation of DDR2+ CSCs into suture sites was sufficient to induce fusion, and this phenotype was prevented by co-transplantation of CTSK+ CSCs. Lastly, the human counterparts of DDR2+ CSCs and CTSK+ CSCs are present in calvarial surgical specimens and display conserved functional properties in xenograft assays. The interaction between these two stem cell populations provides a new biologic interface to modulate calvarial mineralization and suture patency.

scholarly journals The Cancer Stem Cell in Hepatocellular Carcinoma

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 684 ◽  
Author(s):  
Lucas-Alexander Schulte ◽  
Juan Carlos López-Gil ◽  
Bruno Sainz ◽  
Patrick C. Hermann
Keyword(s):  
Hepatocellular Carcinoma ◽  
Stem Cell ◽  
Cancer Stem Cell ◽  
Tumor Cells ◽  
Tumor Recurrence ◽  
Cellular Heterogeneity ◽  
Special Focus ◽  
Therapeutic Approaches ◽  
Hierarchical Tree ◽  
Cell Lineages

The recognition of intra-tumoral cellular heterogeneity has given way to the concept of the cancer stem cell (CSC). According to this concept, CSCs are able to self-renew and differentiate into all of the cancer cell lineages present within the tumor, placing the CSC at the top of a hierarchical tree. The observation that these cells—in contrast to bulk tumor cells—are able to exclusively initiate new tumors, initiate metastatic spread and resist chemotherapy implies that CSCs are solely responsible for tumor recurrence and should be therapeutically targeted. Toward this end, dissecting and understanding the biology of CSCs should translate into new clinical therapeutic approaches. In this article, we review the CSC concept in cancer, with a special focus on hepatocellular carcinoma.

scholarly journals A single cell atlas of human teeth

2021 ◽  
Author(s):  
Pierfrancesco Pagella ◽  
Laura de Vargas Roditi ◽  
Bernd Stadlinger ◽  
Andreas E. Moor ◽  
Thimios A. Mitsiadis
Keyword(s):  
Stem Cell ◽  
Single Cell ◽  
Cellular Heterogeneity ◽  
Cell Populations ◽  
Therapeutic Approaches ◽  
Human Teeth ◽  
Functional Differences ◽  
Potential Source ◽  
Stem Cell Populations ◽  
Transcriptional Landscape

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.

scholarly journals Patterns of Cell Division and the Risk of Cancer

Genetics ◽  
2003 ◽  
Vol 163 (4) ◽  
pp. 1527-1532 ◽  
Author(s):  
Steven A Frank ◽  
Yoh Iwasa ◽  
Martin A Nowak
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Basal Layer ◽  
Mutation Rates ◽  
Tissue Architecture ◽  
Cell Lineages ◽  
Cell Mutation ◽  
Long Stem ◽  
Risk Of Cancer ◽  
Transit Cell

Abstract Epidermal and intestinal tissues divide throughout life to replace lost surface cells. These renewing tissues have long-lived basal stem cell lineages that divide many times, each division producing one stem cell and one transit cell. The transit cell divides a limited number of times, producing cells that move up from the basal layer and eventually slough off from the surface. If mutation rates are the same in stem and transit divisions, we show that minimal cancer risk is obtained by using the fewest possible stem divisions subject to the constraints imposed by the need to renew the tissue. In this case, stem cells are a necessary risk imposed by the constraints of tissue architecture. Cairns suggested that stem cells may have lower mutation rates than transit cells do. We develop a mathematical model to study the consequences of different stem and transit mutation rates. Our model shows that stem cell mutation rates two or three orders of magnitude less than transit mutation rates may favor relatively more stem divisions and fewer transit divisions, perhaps explaining how renewing tissues allocate cell divisions between long stem and short transit lineages.

scholarly journals Osteoclasts promote the formation of hematopoietic stem cell niches in the bone marrow

2012 ◽  
Vol 209 (3) ◽  
pp. 537-549 ◽  
Author(s):  
Anna Mansour ◽  
Grazia Abou-Ezzi ◽  
Ewa Sitnicka ◽  
Sten Eirik W. Jacobsen ◽  
Abdelilah Wakkach ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Endochondral Ossification ◽  
Osteoblastic Differentiation ◽  
Hematopoietic Stem ◽  
Mesenchymal Progenitors ◽  
Hsc Niche ◽  
Niche Formation

Formation of the hematopoietic stem cell (HSC) niche in bone marrow (BM) is tightly associated with endochondral ossification, but little is known about the mechanisms involved. We used the oc/oc mouse, a mouse model with impaired endochondral ossification caused by a loss of osteoclast (OCL) activity, to investigate the role of osteoblasts (OBLs) and OCLs in the HSC niche formation. The absence of OCL activity resulted in a defective HSC niche associated with an increased proportion of mesenchymal progenitors but reduced osteoblastic differentiation, leading to impaired HSC homing to the BM. Restoration of OCL activity reversed the defect in HSC niche formation. Our data demonstrate that OBLs are required for establishing HSC niches and that osteoblastic development is induced by OCLs. These findings broaden our knowledge of the HSC niche formation, which is critical for understanding normal and pathological hematopoiesis.

scholarly journals Chromatin and transcription factor profiling in rare stem cell populations using CUT&Tag

2021 ◽  
Vol 2 (3) ◽  
pp. 100751
Author(s):  
Yuefeng Li ◽  
Kiran Nakka ◽  
Thomas Olender ◽  
Philippe Gingras-Gelinas ◽  
Matthew Man-Kin Wong ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Stem Cell ◽  
Cell Populations ◽  
Stem Cell Populations

Notch Signaling Is Required to Maintain All Neural Stem Cell Populations – Irrespective of Spatial or Temporal Niche

2006 ◽  
Vol 28 (1-2) ◽  
pp. 34-48 ◽  
Author(s):  
Tania O. Alexson ◽  
Seiji Hitoshi ◽  
Brenda L. Coles ◽  
Alan Bernstein ◽  
Derek van der Kooy
Keyword(s):  
Stem Cell ◽  
Notch Signaling ◽  
Neural Stem Cell ◽  
Cell Populations ◽  
Temporal Niche ◽  
Stem Cell Populations

scholarly journals Simultaneous Isolation of Three Different Stem Cell Populations from Murine Skin

PLoS ONE ◽  
2015 ◽  
Vol 10 (10) ◽  
pp. e0140143 ◽  
Author(s):  
Maria Fernanda Forni ◽  
Aline Ramos Maia Lobba ◽  
Alexandre Hamilton Pereira Ferreira ◽  
Mari Cleide Sogayar
Keyword(s):  
Stem Cell ◽  
Cell Populations ◽  
Stem Cell Populations

scholarly journals Quiescent, Slow-Cycling Stem Cell Populations in Cancer: A Review of the Evidence and Discussion of Significance

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Nathan Moore ◽  
Stephen Lyle
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Adult Stem Cells ◽  
Cell Populations ◽  
Proliferative Potential ◽  
Cell Cycle Regulators ◽  
Slow Cycling ◽  
Stem Cell Populations

Long-lived cancer stem cells (CSCs) with indefinite proliferative potential have been identified in multiple epithelial cancer types. These cells are likely derived from transformed adult stem cells and are thought to share many characteristics with their parental population, including a quiescent slow-cycling phenotype. Various label-retaining techniques have been used to identify normal slow cycling adult stem cell populations and offer a unique methodology to functionally identify and isolate cancer stem cells. The quiescent nature of CSCs represents an inherent mechanism that at least partially explains chemotherapy resistance and recurrence in posttherapy cancer patients. Isolating and understanding the cell cycle regulatory mechanisms of quiescent cancer cells will be a key component to creation of future therapies that better target CSCs and totally eradicate tumors. Here we review the evidence for quiescent CSC populations and explore potential cell cycle regulators that may serve as future targets for elimination of these cells.

scholarly journals Activation of two distinct Sox9-EGFP-expressing intestinal stem cell populations during crypt regeneration after irradiation

2012 ◽  
Vol 302 (10) ◽  
pp. G1111-G1132 ◽  
Author(s):  
Laurianne Van Landeghem ◽  
M. Agostina Santoro ◽  
Adrienne E. Krebs ◽  
Amanda T. Mah ◽  
Jeffrey J. Dehmer ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Populations ◽  
Intestinal Epithelial ◽  
P53 Signaling ◽  
Reporter Mice ◽  
Radiation Induced ◽  
Molecular Phenotypes ◽  
Stem Cell Populations ◽  
Induced Changes

Recent identification of intestinal epithelial stem cell (ISC) markers and development of ISC reporter mice permit visualization and isolation of regenerating ISCs after radiation to define their functional and molecular phenotypes. Previous studies in uninjured intestine of Sox9-EGFP reporter mice demonstrate that ISCs express low levels of Sox9-EGFP (Sox9-EGFP Low), whereas enteroendocrine cells (EEC) express high levels of Sox9-EGFP (Sox9-EGFP High). We hypothesized that Sox9-EGFP Low ISCs would expand after radiation, exhibit enhanced proliferative capacities, and adopt a distinct gene expression profile associated with rapid proliferation. Sox9-EGFP mice were given 14 Gy abdominal radiation and studied between days 3 and 9 postradiation. Radiation-induced changes in number, growth, and transcriptome of the different Sox9-EGFP cell populations were determined by histology, flow cytometry, in vitro culture assays, and microarray. Microarray confirmed that nonirradiated Sox9-EGFP Low cells are enriched for Lgr5 mRNA and mRNAs enriched in Lgr5-ISCs and identified additional putative ISC markers. Sox9-EGFP High cells were enriched for EEC markers, as well as Bmi1 and Hopx, which are putative markers of quiescent ISCs. Irradiation caused complete crypt loss, followed by expansion and hyperproliferation of Sox9-EGFP Low cells. From nonirradiated intestine, only Sox9-EGFP Low cells exhibited ISC characteristics of forming organoids in culture, whereas during regeneration both Sox9-EGFP Low and High cells formed organoids. Microarray demonstrated that regenerating Sox9-EGFP High cells exhibited transcriptomic changes linked to p53-signaling and ISC-like functions including DNA repair and reduced oxidative metabolism. These findings support a model in which Sox9-EGFP Low cells represent active ISCs, Sox9-EGFP High cells contain radiation-activatable cells with ISC characteristics, and both participate in crypt regeneration.

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