scholarly journals Role of Signaling Pathways during Cardiomyocyte Differentiation of Mesenchymal Stem Cells

Cardiology ◽  
2021 ◽  
Author(s):  
Leila Soltani ◽  
Amir Hossein Mahdavi
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Signaling Pathways ◽  
Heart Development ◽  
Molecular Mechanisms ◽  
Adipogenic Differentiation ◽  
Cardiomyocyte Differentiation ◽  
Multipotent Stem Cells ◽  
Promising Source

Multipotent stem cells, including mesenchymal stem cells (MSCs), represent a promising source to be used by regenerative medicine. They are capable of performing myogenic, chondrogenic, osteogenic and adipogenic differentiation. Also, MSCs are characterized by the expression of multiple surface antigens, but none of them appears to be particularly expressed on MSCs. Moreover, the prospect of monitoring and controlling MSC differentiation is a scientifically crucial regulatory and clinical requirement. Different transcription factors and signaling pathways are involved in cardiomyocyte differentiation. Due to the paucity of studies exclusively focused on cardiomyocyte differentiation of MSCs, present study aims at describing the roles of various signaling pathways (FGF, TGF, Wnt, Notch, etc.) in cardiomyocytes differentiation of MSCs. Understanding the signaling pathways that control the commitment and differentiation of cardiomyocyte cells not only will expand our basic understanding of molecular mechanisms of heart development, but also will enable us to develop therapeutic means of intervention in cardiovascular diseases.

Caveolin-1 Plays an Important Role in the Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells into Cardiomyocytes

Cardiology ◽  
2016 ◽  
Vol 136 (1) ◽  
pp. 40-48 ◽  
Author(s):  
Ying Chen ◽  
Chunxia Wang ◽  
Qiang Huang ◽  
Dan Wu ◽  
Jianing Cao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Molecular Mechanisms ◽  
Control Group ◽  
Marker Genes ◽  
Caveolin 1 ◽  
Stat3 Phosphorylation ◽  
Promising Source

Objectives: Accumulating evidence has demonstrated that bone marrow-derived mesenchymal stem cells (BMSCs) may transdifferentiate into cardiomyocytes, making BMSCs a promising source of cardiomyocytes for transplantation. However, little is known about the molecular mechanisms underlying myogenic conversion of BMSCs. Methods: This study was designed to investigate the functional role of caveolin-1 in the cardiomyocyte differentiation of BMSCs and to explore the potential underlying molecular mechanisms. Results: BMSC differentiation was induced by treatment with 10 μM 5-azacytidine, and immunofluorescence assay showed that the expression of cardiomyocyte marker cardiac troponin T (cTnT) was significantly increased compared with a control group. Meanwhile, an increased caveolin-1 expression was found during the 5-azacytidine-induced BMSC differentiation. Additionally, the role of caveolin-1 in the differentiation process was then studied by using caveolin-1 siRNAs. We found that silencing caveolin-1 during induction remarkably enhanced the expression of cardiomyocyte marker genes, including cTnT, Nkx2.5 (cardiac-specific transcription factor), α-cardiac actin and α-myosin heavy chain (α-MHC). Moreover, we observed that downregulation of caveolin-1 was accompanied by inhibition of signal transducer and activator of transcription 3 (STAT3) phosphorylation. Conclusions: Taken together, these findings demonstrate that caveolin-1 plays an important role in the differentiation of BMSCs into cardiomyocytes in conjunction with the STAT3 pathway.

scholarly journals The Cross-Talk between Mesenchymal Stem Cells and Immune Cells in Tissue Repair and Regeneration

2021 ◽  
Vol 22 (5) ◽  
pp. 2472
Author(s):  
Carl Randall Harrell ◽  
Valentin Djonov ◽  
Vladislav Volarevic
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Immune Cells ◽  
Tissue Repair ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Multipotent Stem Cells ◽  
Tissue Repair And Regeneration ◽  
Almost All ◽  
And Function

Mesenchymal stem cells (MSCs) are self-renewable, rapidly proliferating, multipotent stem cells which reside in almost all post-natal tissues. MSCs possess potent immunoregulatory properties and, in juxtacrine and paracrine manner, modulate phenotype and function of all immune cells that participate in tissue repair and regeneration. Additionally, MSCs produce various pro-angiogenic factors and promote neo-vascularization in healing tissues, contributing to their enhanced repair and regeneration. In this review article, we summarized current knowledge about molecular mechanisms that regulate the crosstalk between MSCs and immune cells in tissue repair and regeneration.

scholarly journals Akt signaling is activated by TGFβ2 and impacts tenogenic induction of mesenchymal stem cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sophia K. Theodossiou ◽  
Jett B. Murray ◽  
LeeAnn A. Hold ◽  
Jeff M. Courtright ◽  
Anne M. Carper ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Signaling Pathways ◽  
Transforming Growth Factor ◽  
Akt Signaling ◽  
Cell Alignment ◽  
Limited Information ◽  
Akt Inhibitor ◽  
Tenogenic Differentiation

Abstract Background Tissue engineered and regenerative approaches for treating tendon injuries are challenged by the limited information on the cellular signaling pathways driving tenogenic differentiation of stem cells. Members of the transforming growth factor (TGF) β family, particularly TGFβ2, play a role in tenogenesis, which may proceed via Smad-mediated signaling. However, recent evidence suggests some aspects of tenogenesis may be independent of Smad signaling, and other pathways potentially involved in tenogenesis are understudied. Here, we examined the role of Akt/mTORC1/P70S6K signaling in early TGFβ2-induced tenogenesis of mesenchymal stem cells (MSCs) and evaluated TGFβ2-induced tenogenic differentiation when Smad3 is inhibited. Methods Mouse MSCs were treated with TGFβ2 to induce tenogenesis, and Akt or Smad3 signaling was chemically inhibited using the Akt inhibitor, MK-2206, or the Smad3 inhibitor, SIS3. Effects of TGFβ2 alone and in combination with these inhibitors on the activation of Akt signaling and its downstream targets mTOR and P70S6K were quantified using western blot analysis, and cell morphology was assessed using confocal microscopy. Levels of the tendon marker protein, tenomodulin, were also assessed. Results TGFβ2 alone activated Akt signaling during early tenogenic induction. Chemically inhibiting Akt prevented increases in tenomodulin and attenuated tenogenic morphology of the MSCs in response to TGFβ2. Chemically inhibiting Smad3 did not prevent tenogenesis, but appeared to accelerate it. MSCs treated with both TGFβ2 and SIS3 produced significantly higher levels of tenomodulin at 7 days and morphology appeared tenogenic, with localized cell alignment and elongation. Finally, inhibiting Smad3 did not appear to impact Akt signaling, suggesting that Akt may allow TGFβ2-induced tenogenesis to proceed during disruption of Smad3 signaling. Conclusions These findings show that Akt signaling plays a role in TGFβ2-induced tenogenesis and that tenogenesis of MSCs can be initiated by TGFβ2 during disruption of Smad3 signaling. These findings provide new insights into the signaling pathways that regulate tenogenic induction in stem cells.

scholarly journals Loss of Notch3 Signaling Enhances Osteogenesis of Mesenchymal Stem Cells from Mandibular Torus

2016 ◽  
Vol 96 (3) ◽  
pp. 347-354 ◽  
Author(s):  
X.W. Dou ◽  
W. Park ◽  
S. Lee ◽  
Q.Z. Zhang ◽  
L.R. Carrasco ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Osteogenic Differentiation ◽  
Transcriptional Activation ◽  
Target Genes ◽  
Adipogenic Differentiation ◽  
Underlying Mechanism ◽  
Jaw Bone ◽  
Downstream Target

Mandibular torus (MT) is a common intraoral osseous outgrowth located on the lingual surface of the mandible. Histologic features include hyperplastic bone consisting of mature cortical and trabecular bone. Some theories on the etiology of MT have been postulated, such as genetic factors, masticatory hyperfunction, trauma, and continued growth, but the underlying mechanism remains largely unknown. In this study, we investigated the potential role of mesenchymal stem cells (MSCs) derived from human MT in the pathogenesis of bone outgrowth. We demonstrated that MT harbored a distinct subpopulation of MSCs, with enhanced osteogenic and decreased adipogenic differentiation capacities, as compared with their counterparts from normal jaw bone. The increased osteogenic differentiation of mandibular torus MSCs was associated with the suppression of Notch3 signaling and its downstream target genes, Jag1 and Hey1, and a reciprocal increase in the transcriptional activation of ATF4 and NFATc1 genes. Targeted knockdown of Notch3 expression by transient siRNA transfection promoted the expression of osteogenic transcription factors in normal jaw bone MSCs. Our data suggest that the loss of Notch3 signaling may contribute partly to bone outgrowth in MT, as mediated by enhanced MSC-driven osteogenic differentiation in the jaw bone.

scholarly journals Obesity-Induced Methylation of Osteopontin Contributes to Adipogenic Differentiation of Adipose-Derived Mesenchymal Stem Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Min Tang ◽  
Rui Chen ◽  
Hao Wang ◽  
Guowei Sun ◽  
Fan Yin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Adipogenic Differentiation ◽  
Underlying Mechanism ◽  
Human Beings ◽  
Fatty Livers ◽  
Novel Target ◽  
Adipose Mass

Obesity is a major risk factor for many chronic diseases, including diabetes, fatty livers, and cancer. Expansion of the adipose mass has been shown to be related to adipogenic differentiation of adipose-derived mesenchymal stem cells (ASCs). However, the underlying mechanism of this effect has yet to be elucidated. We found that osteopontin (OPN) is downregulated in ASCs and adipose tissues of obese mice and overweight human beings because of methylation on its promoter, indicating that OPN may affect the development of obesity. Silencing of OPN in wild-type ASCs promotes adipogenic differentiation, while reexpression of OPN reduced adipogenic differentiation in OPN−/− ASCs. The role of extracellular OPN in ASC differentiation was further demonstrated by supplementation and neutralization of OPN. Additionally, OPN suppresses adipogenic differentiation in ASCs through the C/EBP pathways. Consistent with these in vitro results, by intravenous injection of OPN-expressing adenovirus to the mice, we found OPN can delay the development of obesity and improve insulin sensitivity. Therefore, our study demonstrates an important role of OPN in regulating the development of obesity, indicating OPN might be a novel target to attenuate obesity and its complications.

scholarly journals Mesenchymal Stem Cells and Extracellular Vesicles in Osteosarcoma Pathogenesis and Therapy

2021 ◽  
Vol 22 (20) ◽  
pp. 11035
Author(s):  
Virinder Kaur Sarhadi ◽  
Ravindra Daddali ◽  
Riitta Seppänen-Kaijansinkko
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Extracellular Vesicles ◽  
Poor Prognosis ◽  
Paracrine Signaling ◽  
Mediated Communication ◽  
Multipotent Stem Cells ◽  
Genetic Complexity ◽  
Potential Applications

Osteosarcoma (OS) is an aggressive bone tumor that mainly affects children and adolescents. OS has a strong tendency to relapse and metastasize, resulting in poor prognosis and survival. The high heterogeneity and genetic complexity of OS make it challenging to identify new therapeutic targets. Mesenchymal stem cells (MSCs) are multipotent stem cells that can differentiate into adipocytes, osteoblasts, or chondroblasts. OS is thought to originate at some stage in the differentiation process of MSC to pre-osteoblast or from osteoblast precursors. MSCs contribute to OS progression by interacting with tumor cells via paracrine signaling and affect tumor cell proliferation, invasion, angiogenesis, immune response, and metastasis. Extracellular vesicles (EVs), secreted by OS cells and MSCs in the tumor microenvironment, are crucial mediators of intercellular communication, driving OS progression by transferring miRNAs/RNA and proteins to other cells. MSC-derived EVs have both pro-tumor and anti-tumor effects on OS progression. MSC-EVs can be also engineered to deliver anti-tumor cargo to the tumor site, which offers potential applications in MSC-EV-based OS treatment. In this review, we highlight the role of MSCs in OS, with a focus on EV-mediated communication between OS cells and MSCs and their role in OS pathogenesis and therapy.

scholarly journals RSP5 Positively Regulates the Osteogenic Differentiation of Mesenchymal Stem Cells by Activating the K63-Linked Ubiquitination of Akt

2020 ◽  
Vol 2020 ◽  
pp. 1-13 ◽  
Author(s):  
Changxiang Liang ◽  
Guoyan Liang ◽  
Xiaoqing Zheng ◽  
Yongxiong Huang ◽  
Shuaihao Huang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Osteogenic Differentiation ◽  
Bone Repair ◽  
Multipotent Stem Cells ◽  
Cell Therapies ◽  
Ubiquitin Protein Ligase ◽  
Promising Target ◽  
Further Development

Mesenchymal stem cells (MSCs) are multipotent stem cells that have a strong osteogenic differentiation capacity. However, the molecular mechanism underlying the osteogenic differentiation of MSCs remains largely unknown and thus hinders further development of MSC-based cell therapies for bone repair in the clinic. RSP5, also called NEDD4L (NEDD4-like E3 ubiquitin protein ligase), belongs to the HECT (homologous to E6-AP carboxyl terminus) domain-containing E3 ligase family. Nevertheless, although many studies have been conducted to elucidate the role of RSP5 in various biological processes, its effect on osteogenesis remains elusive. In this study, we demonstrated that the expression of RSP5 was elevated during the osteogenesis of MSCs and positively regulated the osteogenic capacity of MSCs by inducing K63-linked polyubiquitination and activation of the Akt pathway. Taken together, our findings suggest that RSP5 may be a promising target to improve therapeutic efficiency by using MSCs for bone regeneration and repair.

scholarly journals Quantitative proteomics identify DAB2 as a cardiac developmental regulator that inhibits WNT/β-catenin signaling

2016 ◽  
Vol 113 (4) ◽  
pp. 1002-1007 ◽  
Author(s):  
Peter Hofsteen ◽  
Aaron M. Robitaille ◽  
Daniel Patrick Chapman ◽  
Randall T. Moon ◽  
Charles E. Murry
Keyword(s):  
Stem Cells ◽  
Heart Development ◽  
Quantitative Proteomics ◽  
Time Course ◽  
Molecular Mechanisms ◽  
Embryonic Stem ◽  
Label Free ◽  
Cardiomyocyte Differentiation ◽  
Human Stem Cells ◽  
Cardiomyocyte Number

To reveal the molecular mechanisms involved in cardiac lineage determination and differentiation, we quantified the proteome of human embryonic stem cells (hESCs), cardiac progenitor cells (CPCs), and cardiomyocytes during a time course of directed differentiation by label-free quantitative proteomics. This approach correctly identified known stage-specific markers of cardiomyocyte differentiation, including SRY-box2 (SOX2), GATA binding protein 4 (GATA4), and myosin heavy chain 6 (MYH6). This led us to determine whether our proteomic screen could reveal previously unidentified mediators of heart development. We identified Disabled 2 (DAB2) as one of the most dynamically expressed proteins in hESCs, CPCs, and cardiomyocytes. We used clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) mutagenesis in zebrafish to assess whether DAB2 plays a functional role during cardiomyocyte differentiation. We found that deletion of Dab2 in zebrafish embryos led to a significant reduction in cardiomyocyte number and increased endogenous WNT/β-catenin signaling. Furthermore, the Dab2-deficient defects in cardiomyocyte number could be suppressed by overexpression of dickkopf 1 (DKK1), an inhibitor of WNT/β-catenin signaling. Thus, inhibition of WNT/β-catenin signaling by DAB2 is essential for establishing the correct number of cardiomyocytes in the developing heart. Our work demonstrates that quantifying the proteome of human stem cells can identify previously unknown developmental regulators.

scholarly journals Mesenchymal Stem Cells Regulate the Innate and Adaptive Immune Responses Dampening Arthritis Progression

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
R. A. Contreras ◽  
F. E. Figueroa ◽  
F. Djouad ◽  
P. Luz-Crawford
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Therapeutic Potential ◽  
Multipotent Stem Cells ◽  
Immune Systems ◽  
Adaptive Immune ◽  
Adaptive Immune Systems

Mesenchymal stem cells (MSCs) are multipotent stem cells that are able to immunomodulate cells from both the innate and the adaptive immune systems promoting an anti-inflammatory environment. During the last decade, MSCs have been intensively studiedin vitroandin vivoin experimental animal model of autoimmune and inflammatory disorders. Based on these studies, MSCs are currently widely used for the treatment of autoimmune diseases such as rheumatoid arthritis (RA) characterized by complex deregulation of the immune systems. However, the therapeutic properties of MSCs in arthritis are still controverted. These controversies might be due to the diversity of MSC sources and isolation protocols used, the time, the route and dose of MSC administration, the variety of the mechanisms involved in the MSCs suppressive effects, and the complexity of arthritis pathogenesis. In this review, we discuss the role of the interactions between MSCs and the different immune cells associated with arthritis pathogenesis and the possible means described in the literature that could enhance MSCs therapeutic potential counteracting arthritis development and progression.

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