scholarly journals A MEKK1 – JNK mitogen activated kinase (MAPK) cascade module is active in Echinococcus multilocularis stem cells

2021 ◽  
Vol 15 (12) ◽  
pp. e0010027
Author(s):  
Kristin Stoll ◽  
Monika Bergmann ◽  
Markus Spiliotis ◽  
Klaus Brehm
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Growth Factor ◽  
Stress Responses ◽  
Echinococcus Multilocularis ◽  
Tyrosine Kinases ◽  
Cell Function ◽  
Mapk Cascade ◽  
Tyrosine Kinase Receptor ◽  
Mapk Kinase

Background The metacestode larval stage of the fox-tapeworm Echinococcus multilocularis causes alveolar echinococcosis by tumour-like growth within the liver of the intermediate host. Metacestode growth and development is stimulated by host-derived cytokines such as insulin, fibroblast growth factor, and epidermal growth factor via activation of cognate receptor tyrosine kinases expressed by the parasite. Little is known, however, concerning signal transmission to the parasite nucleus and cross-reaction with other parasite signalling systems. Methodology/Principal findings Using bioinformatic approaches, cloning, and yeast two-hybrid analyses we identified a novel mitogen-activated kinase (MAPK) cascade module that consists of E. multilocularis orthologs of the tyrosine kinase receptor interactor Growth factor receptor-bound 2, EmGrb2, the MAPK kinase kinase EmMEKK1, a novel MAPK kinase, EmMKK3, and a close homolog to c-Jun N-terminal kinase (JNK), EmMPK3. Whole mount in situ hybridization analyses indicated that EmMEKK1 and EmMPK3 are both expressed in E. multilocularis germinative (stem) cells but also in differentiated or differentiating cells. Treatment with the known JNK inhibitor SP600125 led to a significantly reduced formation of metacestode vesicles from stem cells and to a specific reduction of proliferating stem cells in mature metacestode vesicles. Conclusions/Significance We provide evidence for the expression of a MEKK1-JNK MAPK cascade module which, in mammals, is crucially involved in stress responses, cytoskeletal rearrangements, and apoptosis, in E. multilocularis stem cells. Inhibitor studies indicate an important role of JNK signalling in E. multilocularis stem cell survival and/or maintenance. Our data are relevant for molecular and cellular studies into crosstalk signalling mechanisms that govern Echinococcus stem cell function and introduce the JNK signalling cascade as a possible target of chemotherapeutics against echinococcosis.

scholarly journals Antioxidant Effects of Caffeic Acid Lead to Protection of Drosophila Intestinal Stem Cell Aging

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiao Sheng ◽  
Yuedan Zhu ◽  
Juanyu Zhou ◽  
La Yan ◽  
Gang Du ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Caffeic Acid ◽  
Stress Responses ◽  
Adult Stem Cells ◽  
Cell Function ◽  
Cell Aging ◽  
Positive Effects ◽  
Age Related ◽  
Tissue Aging

The dysfunction or exhaustion of adult stem cells during aging is closely linked to tissue aging and age-related diseases. Circumventing this aging-related exhaustion of adult stem cells could significantly alleviate the functional decline of organs. Therefore, identifying small molecular compounds that could prevent the age-related decline of stem cell function is a primary goal in anti-aging research. Caffeic acid (CA), a phenolic compound synthesized in plants, offers substantial health benefits for multiple age-related diseases and aging. However, the effects of CA on adult stem cells remain largely unknown. Using the Drosophila midgut as a model, this study showed that oral administration with CA significantly delayed age-associated Drosophila gut dysplasia caused by the dysregulation of intestinal stem cells (ISCs) upon aging. Moreover, administering CA retarded the decline of intestinal functions in aged Drosophila and prevented hyperproliferation of age-associated ISC by suppressing oxidative stress-associated JNK signaling. On the other hand, CA supplementation significantly ameliorated the gut hyperplasia defect and reduced environmentally induced mortality, revealing the positive effects of CA on tolerance to stress responses. Taken together, our findings report a crucial role of CA in delaying age-related changes in ISCs of Drosophila.

Abstract 242: Bone-derived Stem Cells Repair The Heart After Myocardial Infarction Through Transdifferentiation And Paracrine Signaling Mechanisms

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Jason M Duran ◽  
Catherine A Makarewich ◽  
Thomas E Sharp ◽  
Timothy Starosta ◽  
Fang Zhu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Stem Cell ◽  
Growth Factor ◽  
Cardiac Function ◽  
Cell Function ◽  
Calcium Currents ◽  
Border Zone ◽  
Sham Operation ◽  
Paracrine Factors

Rationale: Autologous bone marrow- or cardiac-derived stem cell therapy for heart disease has demonstrated safety and efficacy in clinical trials but has only offered limited functional improvements. Finding the optimal stem cell type best suited for cardiac regeneration remains a key goal toward improving clinical outcomes. Objective: To determine the mechanism by which novel bone-derived stem cells support the injured heart. Methods and Results: Cortical bone stem cells (CBSCs) were isolated from EGFP+ transgenic mice and were shown to express c-kit and Sca-1 as well as 8 paracrine factors involved in cardioprotection, angiogenesis and stem cell function. Wild-type C57BL/6 mice underwent sham operation (n=21) or myocardial infarction (MI) with injection of CBSCs (n=57) or saline (n=59). Cardiac function was monitored using echocardiography with strain analysis. EGFP+ stem cells in vivo were shown to express only 2/8 factors tested (basic fibroblast growth factor and vascular endothelial growth factor) and this expression was associated with increased neovascularization of the infarct border zone. CBSC therapy improved survival, cardiac function, attenuated adverse remodeling, and decreased infarct size relative to saline-treated MI controls. By 6 weeks post-MI, EGFP+ cardiomyocytes, vascular smooth muscle cells and endothelial cells could be identified on histology. Isolated EGFP+ myocytes were smaller, more frequently mononucleated, and demonstrated fractional shortening and calcium currents indistinguishable from EGFP- myocytes from the same hearts. Conclusions: CBSCs improve survival, cardiac function, and attenuate remodeling by 1) secreting the proangiogenic factors bFGF and VEGF (stimulating endogenous neovascularization), and 2) differentiating into functional adult myocytes and vascular cells.

scholarly journals Bone-Derived Stem Cells Repair the Heart After Myocardial Infarction Through Transdifferentiation and Paracrine Signaling Mechanisms

2013 ◽  
Vol 113 (5) ◽  
pp. 539-552 ◽  
Author(s):  
Jason M. Duran ◽  
Catherine A. Makarewich ◽  
Thomas E. Sharp ◽  
Timothy Starosta ◽  
Fang Zhu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Stem Cell ◽  
Growth Factor ◽  
Cardiac Function ◽  
Cell Function ◽  
Fluorescent Protein ◽  
Border Zone ◽  
Sham Operation ◽  
Paracrine Factors

Rationale: Autologous bone marrow–derived or cardiac-derived stem cell therapy for heart disease has demonstrated safety and efficacy in clinical trials, but functional improvements have been limited. Finding the optimal stem cell type best suited for cardiac regeneration is the key toward improving clinical outcomes. Objective: To determine the mechanism by which novel bone-derived stem cells support the injured heart. Methods and Results: Cortical bone–derived stem cells (CBSCs) and cardiac-derived stem cells were isolated from enhanced green fluorescent protein (EGFP+) transgenic mice and were shown to express c-kit and Sca-1 as well as 8 paracrine factors involved in cardioprotection, angiogenesis, and stem cell function. Wild-type C57BL/6 mice underwent sham operation (n=21) or myocardial infarction with injection of CBSCs (n=67), cardiac-derived stem cells (n=36), or saline (n=60). Cardiac function was monitored using echocardiography. Only 2/8 paracrine factors were detected in EGFP+ CBSCs in vivo (basic fibroblast growth factor and vascular endothelial growth factor), and this expression was associated with increased neovascularization of the infarct border zone. CBSC therapy improved survival, cardiac function, regional strain, attenuated remodeling, and decreased infarct size relative to cardiac-derived stem cells– or saline-treated myocardial infarction controls. By 6 weeks, EGFP+ cardiomyocytes, vascular smooth muscle, and endothelial cells could be identified in CBSC-treated, but not in cardiac-derived stem cells–treated, animals. EGFP+ CBSC-derived isolated myocytes were smaller and more frequently mononucleated, but were functionally indistinguishable from EGFP− myocytes. Conclusions: CBSCs improve survival, cardiac function, and attenuate remodeling through the following 2 mechanisms: (1) secretion of proangiogenic factors that stimulate endogenous neovascularization, and (2) differentiation into functional adult myocytes and vascular cells.

scholarly journals Loss of tyrosine kinase receptor Ephb2 impairs proliferation and stem cell activity of spermatogonia in culture†

2019 ◽  
Vol 102 (4) ◽  
pp. 950-962
Author(s):  
Thierry N’Tumba-Byn ◽  
Makiko Yamada ◽  
Marco Seandel
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Function ◽  
Cultured Cells ◽  
Cell Activity ◽  
Mapk Signaling ◽  
Tyrosine Kinase Receptor ◽  
Wild Type ◽  
Stem Cell Activity

Abstract Germline stem and progenitor cells can be extracted from the adult mouse testis and maintained long-term in vitro. Yet, the optimal culture conditions for preserving stem cell activity are unknown. Recently, multiple members of the Eph receptor family were detected in murine spermatogonia, but their roles remain obscure. One such gene, Ephb2, is crucial for maintenance of somatic stem cells and was previously found enriched at the level of mRNA in murine spermatogonia. We detected Ephb2 mRNA and protein in primary adult spermatogonial cultures and hypothesized that Ephb2 plays a role in maintenance of stem cells in vitro. We employed CRISPR-Cas9 targeting and generated stable mutant SSC lines with complete loss of Ephb2. The characteristics of Ephb2-KO cells were interrogated using phenotypic and functional assays. Ephb2-KO SSCs exhibited reduced proliferation compared to wild-type cells, while apoptosis was unaffected. Therefore, we examined whether Ephb2 loss correlates with activity of canonical pathways involved in stem cell self-renewal and proliferation. Ephb2-KO cells had reduced ERK MAPK signaling. Using a lentiviral transgene, Ephb2 expression was rescued in Ephb2-KO cells, which partially restored signaling and proliferation. Transplantation analysis revealed that Ephb2-KO SSCs cultures formed significantly fewer colonies than WT, indicating a role for Ephb2 in preserving stem cell activity of cultured cells. Transcriptome analysis of wild-type and Ephb2-KO SSCs identified Dppa4 and Bnc1 as differentially expressed, Ephb2-dependent genes that are potentially involved in stem cell function. These data uncover for the first time a crucial role for Ephb2 signaling in cultured SSCs.

Stem Cell Function, Self-Renewal, Heterogeneity, and Regenerative Potential in Skeletal Muscle Stem Cells

2012 ◽  
Vol 2 (1) ◽  
pp. 11-21
Author(s):  
Silvia Cristini ◽  
Giulio Alessandri ◽  
Francesco Acerbi ◽  
Daniela Tavian ◽  
Eugenio A. Parati ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Stem Cell ◽  
Cell Function ◽  
Self Renewal ◽  
Muscle Stem Cells ◽  
Skeletal Muscle Stem Cells

Stem Cell Function, Self-Renewal, Heterogeneity, and Regenerative Potential in Skeletal Muscle Stem Cells

2012 ◽  
Vol 2 (1) ◽  
pp. 11-21
Author(s):  
Silvia Cristini ◽  
Giulio Alessandri ◽  
Francesco Acerbi ◽  
Daniela Tavian ◽  
Eugenio A. Parati ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Stem Cell ◽  
Cell Function ◽  
Self Renewal ◽  
Muscle Stem Cells ◽  
Skeletal Muscle Stem Cells

scholarly journals Multiple Roles for Cholinergic Signaling from the Perspective of Stem Cell Function

2021 ◽  
Vol 22 (2) ◽  
pp. 666
Author(s):  
Toshio Takahashi
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Function ◽  
Cell Activity ◽  
Embryonic Stem ◽  
Cholinergic Neurons ◽  
Cell Types ◽  
Proliferative Potential ◽  
True Nature ◽  
Cholinergic Signaling

Stem cells have extensive proliferative potential and the ability to differentiate into one or more mature cell types. The mechanisms by which stem cells accomplish self-renewal provide fundamental insight into the origin and design of multicellular organisms. These pathways allow the repair of damage and extend organismal life beyond that of component cells, and they probably preceded the evolution of complex metazoans. Understanding the true nature of stem cells can only come from discovering how they are regulated. The concept that stem cells are controlled by particular microenvironments, also known as niches, has been widely accepted. Technical advances now allow characterization of the zones that maintain and control stem cell activity in several organs, including the brain, skin, and gut. Cholinergic neurons release acetylcholine (ACh) that mediates chemical transmission via ACh receptors such as nicotinic and muscarinic receptors. Although the cholinergic system is composed of organized nerve cells, the system is also involved in mammalian non-neuronal cells, including stem cells, embryonic stem cells, epithelial cells, and endothelial cells. Thus, cholinergic signaling plays a pivotal role in controlling their behaviors. Studies regarding this signal are beginning to unify our understanding of stem cell regulation at the cellular and molecular levels, and they are expected to advance efforts to control stem cells therapeutically. The present article reviews recent findings about cholinergic signaling that is essential to control stem cell function in a cholinergic niche.

scholarly journals Empowering Muscle Stem Cells for the Treatment of Duchenne Muscular Dystrophy

2021 ◽  
pp. 1-14
Author(s):  
Romina L. Filippelli ◽  
Natasha C. Chang
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Cell Function ◽  
Critical Role ◽  
Membrane Integrity ◽  
Muscle Membrane ◽  
Muscle Stem Cell ◽  
Muscle Stem Cells

Duchenne muscular dystrophy (DMD) is a devastating and debilitating muscle degenerative disease affecting 1 in every 3,500 male births worldwide. DMD is progressive and fatal; accumulated weakening of the muscle tissue leads to an inability to walk and eventual loss of life due to respiratory and cardiac failure. Importantly, there remains no effective cure for DMD. DMD is caused by defective expression of the <i>DMD</i> gene, which encodes for dystrophin, a component of the dystrophin glycoprotein complex. In muscle fibers, this protein complex plays a critical role in maintaining muscle membrane integrity. Emerging studies have shown that muscle stem cells, which are adult stem cells responsible for muscle repair, are also affected in DMD. DMD muscle stem cells do not function as healthy muscle stem cells, and their impairment contributes to disease progression. Deficiencies in muscle stem cell function include impaired establishment of cell polarity leading to defective asymmetric stem cell division, reduced myogenic commitment, impaired differentiation, altered metabolism, and enhanced entry into senescence. Altogether, these findings indicate that DMD muscle stem cells are dysfunctional and have impaired regenerative potential. Although recent advances in adeno-associated vector and antisense oligonucleotide-mediated mechanisms for gene therapy have shown clinical promise, the current therapeutic strategies for muscular dystrophy do not effectively target muscle stem cells and do not address the deficiencies in muscle stem cell function. Here, we discuss the merits of restoring endogenous muscle stem cell function in degenerating muscle as a viable regenerative medicine strategy to mitigate DMD.

scholarly journals Set1 Targets Genes with Essential Identity and Tumor-Suppressing Functions in Planarian Stem Cells

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1182
Author(s):  
Prince Verma ◽  
Court K. M. Waterbury ◽  
Elizabeth M. Duncan
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Mammalian Cells ◽  
Cell Function ◽  
Genotoxic Stress ◽  
Specific Gene ◽  
Cell Identity ◽  
Chromatin Signature ◽  
Lysine Methyltransferase

Tumor suppressor genes (TSGs) are essential for normal cellular function in multicellular organisms, but many TSGs and tumor-suppressing mechanisms remain unknown. Planarian flatworms exhibit particularly robust tumor suppression, yet the specific mechanisms underlying this trait remain unclear. Here, we analyze histone H3 lysine 4 trimethylation (H3K4me3) signal across the planarian genome to determine if the broad H3K4me3 chromatin signature that marks essential cell identity genes and TSGs in mammalian cells is conserved in this valuable model of in vivo stem cell function. We find that this signature is indeed conserved on the planarian genome and that the lysine methyltransferase Set1 is largely responsible for creating it at both cell identity and putative TSG loci. In addition, we show that depletion of set1 in planarians induces stem cell phenotypes that suggest loss of TSG function, including hyperproliferation and an abnormal DNA damage response (DDR). Importantly, this work establishes that Set1 targets specific gene loci in planarian stem cells and marks them with a conserved chromatin signature. Moreover, our data strongly suggest that Set1 activity at these genes has important functional consequences both during normal homeostasis and in response to genotoxic stress.

Developmentally regulated use of alternative promoters creates a novel platelet-derived growth factor receptor transcript in mouse teratocarcinoma and embryonic stem cells

1989 ◽  
Vol 9 (10) ◽  
pp. 4563-4567
Author(s):  
T H Vu ◽  
G R Martin ◽  
P Lee ◽  
D Mark ◽  
A Wang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Embryonic Stem Cells ◽  
Growth Factor ◽  
Short Form ◽  
Embryonic Stem ◽  
Growth Factor Receptor ◽  
Extracellular Domain ◽  
Platelet Derived Growth Factor ◽  
Alternative Promoters

Embryonal carcinoma and embryonic stem cells expressed a novel form of platelet-derived growth factor receptor mRNA which was approximately 1,100 base pairs shorter than the 5.3-kilobase (kb) transcript expressed in fibroblasts and other cell types. The 4.2-kb stem cell transcript was initiated within the genomic region immediately upstream of exon 6 of the 5.3-kb transcript and therefore lacked the first five exons, which encode much of the extracellular domain of the receptor expressed in fibroblasts. In stem cells, the short form was predominant, although both forms were present at low levels. Following differentiation in vitro, expression levels of the long form increased dramatically. These findings suggest that during early embryogenesis, a stem cell-specific promoter is used in a stage- and cell type-specific manner to express a form of the platelet-derived growth factor receptor that lacks much of the extracellular domain and may function independently of ligand.

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