Mammary Epithelial Reconstitution with Gene-Modified Stem Cells Assigns Roles to Stat5 in Luminal Alveolar Cell Fate Decisions, Differentiation, Involution and Mammary Tumor Formation

Any epithelial portion of a normal mouse mammary gland can reproduce an entire functional gland when transplanted into an epithelium-free mammary fat pad. Mouse mammary hyperplasias and tumors are clonal dominant populations and probably represent the progeny of a single transformed cell. Our study provides evidence that single multipotent stem cells positioned throughout the mature fully developed mammary gland have the capacity to produce sufficient differentiated progeny to recapitulate an entire functional gland. Our evidence also demonstrates that these stem cells are self-renewing and are found with undiminished capacities in the newly regenerated gland. We have taken advantage of an experimental model where mouse mammary tumor virus infects mammary epithelial cells and inserts a deoxyribonucleic acid copy(ies) of its genome during replication. The insertions occur randomly within the somatic genome. CzechII mice have no endogenous nucleic acid sequence homology with mouse mammary tumor virus; therefore all viral insertions may be detected by Southern analysis provided a sufficient number of cells contain a specific insertional event. Transplantation of random fragments of infected CzechII mammary gland produced clonal-dominant epithelial populations in epithelium-free mammary fat pads. Serial transplantation of pieces of the clonally derived outgrowths produced second generation glands possessing the same viral insertion sites providing evidence for self-renewal of the original stem cell. Limiting dilution studies with cell cultures derived from third generation clonal outgrowths demonstrated that three multipotent but distinct mammary epithelial progenitors were present in clonally derived mammary epithelial populations. Estimation of the potential number of multipotent epithelial cells that may be evolved from an individual mammary-specific stem cell by self-renewal is in the order of 10(12)-10(13). Therefore, one stem cell might easily account for the renewal of mammary epithelium over several transplant generations.

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Do Neural Stem Cells Have a Choice? Heterogenic Outcome of Cell Fate Acquisition in Different Injury Models

International Journal of Molecular Sciences ◽

10.3390/ijms20020455 ◽

2019 ◽

Vol 20 (2) ◽

pp. 455 ◽

Cited By ~ 3

Author(s):

Felix Beyer ◽

Iria Samper Agrelo ◽

Patrick Küry

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Cell Fate ◽

Ex Vivo ◽

Meta Analysis ◽

Cell Types ◽

Adult Brain ◽

Repair Capacity ◽

Cell Fate Decisions ◽

Limiting Parameters

The adult mammalian central nervous system (CNS) is generally considered as repair restricted organ with limited capacities to regenerate lost cells and to successfully integrate them into damaged nerve tracts. Despite the presence of endogenous immature cell types that can be activated upon injury or in disease cell replacement generally remains insufficient, undirected, or lost cell types are not properly generated. This limitation also accounts for the myelin repair capacity that still constitutes the default regenerative activity at least in inflammatory demyelinating conditions. Ever since the discovery of endogenous neural stem cells (NSCs) residing within specific niches of the adult brain, as well as the description of procedures to either isolate and propagate or artificially induce NSCs from various origins ex vivo, the field has been rejuvenated. Various sources of NSCs have been investigated and applied in current neuropathological paradigms aiming at the replacement of lost cells and the restoration of functionality based on successful integration. Whereas directing and supporting stem cells residing in brain niches constitutes one possible approach many investigations addressed their potential upon transplantation. Given the heterogeneity of these studies related to the nature of grafted cells, the local CNS environment, and applied implantation procedures we here set out to review and compare their applied protocols in order to evaluate rate-limiting parameters. Based on our compilation, we conclude that in healthy CNS tissue region specific cues dominate cell fate decisions. However, although increasing evidence points to the capacity of transplanted NSCs to reflect the regenerative need of an injury environment, a still heterogenic picture emerges when analyzing transplantation outcomes in injury or disease models. These are likely due to methodological differences despite preserved injury environments. Based on this meta-analysis, we suggest future NSC transplantation experiments to be conducted in a more comparable way to previous studies and that subsequent analyses must emphasize regional heterogeneity such as accounting for differences in gray versus white matter.

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Runx1 downregulates stem cell and megakaryocytic transcription programs that support niche interactions

Blood ◽

10.1182/blood-2015-09-668129 ◽

2016 ◽

Vol 127 (26) ◽

pp. 3369-3381 ◽

Cited By ~ 21

Author(s):

Kira Behrens ◽

Ioanna Triviai ◽

Maike Schwieger ◽

Nilgün Tekin ◽

Malik Alawi ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Stem Cell ◽

Cell Adhesion ◽

Cell Fate ◽

Bone Marrow Niche ◽

Cell Fate Decisions ◽

Multipotent Progenitors ◽

Key Points

Key Points Runx1 is a key determinant of megakaryocyte cell-fate decisions in multipotent progenitors. Runx1 downregulates cell-adhesion factors that promote residency of stem cells and megakaryocytes in their bone marrow niche.

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Abstract 3451: Interactions between N-myc and Sox9 promote medulloblastoma and determine cell fate decisions in cerebellar neural stem cells

10.1158/1538-7445.am2011-3451 ◽

2011 ◽

Author(s):

Fredrik J. Swartling ◽

Anders I. Persson ◽

Jasmine Lau ◽

Paul A. Northcott ◽

Matthew R. Grimmer ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Cell Fate ◽

Cell Fate Decisions

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Cancer Stem Cells, Quo Vadis? The Notch Signaling Pathway in Tumor Initiation and Progression

Cells ◽

10.3390/cells9081879 ◽

2020 ◽

Vol 9 (8) ◽

pp. 1879 ◽

Cited By ~ 2

Author(s):

Christian T. Meisel ◽

Cristina Porcheri ◽

Thimios A. Mitsiadis

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Notch Signaling ◽

Signaling Pathway ◽

Cell Fate ◽

Adult Life ◽

Notch Pathway ◽

Notch Signaling Pathway ◽

Fine Tuning ◽

Cell Fate Decisions

The Notch signaling pathway regulates cell proliferation, cytodifferentiation and cell fate decisions in both embryonic and adult life. Several aspects of stem cell maintenance are dependent from the functionality and fine tuning of the Notch pathway. In cancer, Notch is specifically involved in preserving self-renewal and amplification of cancer stem cells, supporting the formation, spread and recurrence of the tumor. As the function of Notch signaling is context dependent, we here provide an overview of its activity in a variety of tumors, focusing mostly on its role in the maintenance of the undifferentiated subset of cancer cells. Finally, we analyze the potential of molecules of the Notch pathway as diagnostic and therapeutic tools against the various cancers.

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Wnt-inhibitory factor 1 dysregulation of the bone marrow niche exhausts hematopoietic stem cells

Blood ◽

10.1182/blood-2010-09-305664 ◽

2011 ◽

Vol 118 (9) ◽

pp. 2420-2429 ◽

Cited By ~ 47

Author(s):

Christoph Schaniel ◽

Dario Sirabella ◽

Jiajing Qiu ◽

Xiaohong Niu ◽

Ihor R. Lemischka ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Wnt Signaling ◽

Cell Fate ◽

Sonic Hedgehog ◽

Hematopoietic Stem ◽

Cell Fate Decisions ◽

Cell Niche ◽

Wnt Inhibitory Factor 1 ◽

Stem Cell Pool

Abstract The role of Wnt signaling in hematopoietic stem cell fate decisions remains controversial. We elected to dysregulate Wnt signaling from the perspective of the stem cell niche by expressing the pan Wnt inhibitor, Wnt inhibitory factor 1 (Wif1), specifically in osteoblasts. Here we report that osteoblastic Wif1 overexpression disrupts stem cell quiescence, leading to a loss of self-renewal potential. Primitive stem and progenitor populations were more proliferative and elevated in bone marrow and spleen, manifesting an impaired ability to maintain a self-renewing stem cell pool. Exhaustion of the stem cell pool was apparent only in the context of systemic stress by chemotherapy or transplantation of wild-type stem cells into irradiated Wif1 hosts. Paradoxically this is mediated, at least in part, by an autocrine induction of canonical Wnt signaling in stem cells on sequestration of Wnts in the environment. Additional signaling pathways are dysregulated in this model, primarily activated Sonic Hedgehog signaling in stem cells as a result of Wif1-induced osteoblastic expression of Sonic Hedgehog. We find that dysregulation of the stem cell niche by overexpression of an individual component impacts other unanticipated regulatory pathways in a combinatorial manner, ultimately disrupting niche mediated stem cell fate decisions.

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Notch signaling in pathogenesis of diseases

American Journal of BioMedicine ◽

10.18081/ajbm/2333-5106-013-12/19-22 ◽

2014 ◽

Vol 2 (1) ◽

pp. 1-13 ◽

Cited By ~ 1

Author(s):

Christense ME ◽

Carolan BS

Keyword(s):

Notch Signaling ◽

Cell Fate ◽

Gene Polymorphisms ◽

Fixed Effects ◽

Vascular System ◽

Meta Analysis ◽

Tumor Formation ◽

Cell Fate Decisions ◽

Pubmed Database ◽

Notch Gene

The Notch signaling pathway functions on cell fate decisions in a variety of different organizations in multicellular organisms, such as the hematopoietic system, nervous system, vascular system, skin and pancreas. In the majority of cases, Notch signaling blocks cell differentiation towards a primary process, and instead, direct them to a second differentiation. Altering the differentiation program or forcing it to remain in the undifferentiated state, there are several human diseases linked to defects in genes involved in Notch signaling, aberrant Notch signaling has been observed in a number of human cancers, suggesting a possible role of Notch signaling in tumor formation. Further, Recent study demonstrated an essential role for Notch1 in the corneal epithelial barrier recovery after wounding. We systematically searched the electronic PubMed database for research articles about Notch gene polymorphisms and diseases up to October 2013. Revman 5.0 software was adopted to conduct the meta-analysis. Crude odds ratio (ORs) and 95% confidence intervals (95% CIs) were calculated by either fixed-effects model or random-effects model. The present meta-analysis suggests that Notch gene polymorphisms are associated with the susceptibility of many diseases especially cancer.

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Notch signaling in pathogenesis of diseases

American Journal of BioMedicine ◽

10.18081/2333-5106-013-12/19-22 ◽

2014 ◽

Vol 2 (1) ◽

pp. 1-4

Keyword(s):

Notch Signaling ◽

Cell Fate ◽

Gene Polymorphisms ◽

Fixed Effects ◽

Vascular System ◽

Meta Analysis ◽

Tumor Formation ◽

Cell Fate Decisions ◽

Pubmed Database ◽

Notch Gene

The Notch signaling pathway functions on cell fate decisions in a variety of different organizations in multicellular organisms, such as the hematopoietic system, nervous system, vascular system, skin and pancreas. In the majority of cases, Notch signaling blocks cell differentiation towards a primary process, and instead, direct them to a second differentiation. Altering the differentiation program or forcing it to remain in the undifferentiated state, there are several human diseases linked to defects in genes involved in Notch signaling, aberrant Notch signaling has been observed in a number of human cancers, suggesting a possible role of Notch signaling in tumor formation. Further, Recent study demonstrated an essential role for Notch1 in the corneal epithelial barrier recovery after wounding. We systematically searched the electronic PubMed database for research articles about Notch gene polymorphisms and diseases up to October 2013. Revman 5.0 software was adopted to conduct the meta-analysis. Crude odds ratio (ORs) and 95% confidence intervals (95% CIs) were calculated by either fixed-effects model or random-effects model. The present meta-analysis suggests that Notch gene polymorphisms are associated with the susceptibility of many diseases especially cancer.

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