Symmetry Breaking during Cell Movement in the Context of Excitability, Kinetic Fine-Tuning and Memory of Pseudopod Formation

The path of moving eukaryotic cells depends on the kinetics and direction of extending pseudopods. Amoeboid cells constantly change their shape with pseudopods extending in different directions. Detailed analysis has revealed that time, place and direction of pseudopod extension are not random, but highly ordered with strong prevalence for only one extending pseudopod, with defined life-times, and with reoccurring events in time and space indicative of memory. Important components are Ras activation and the formation of branched F-actin in the extending pseudopod and inhibition of pseudopod formation in the contractile cortex of parallel F-actin/myosin. In biology, order very often comes with symmetry. In this essay, I discuss cell movement and the dynamics of pseudopod extension from the perspective of symmetry and symmetry changes of Ras activation and the formation of branched F-actin in the extending pseudopod. Combining symmetry of Ras activation with kinetics and memory of pseudopod extension results in a refined model of amoeboid movement that appears to be largely conserved in the fast moving Dictyostelium and neutrophils, the slow moving mesenchymal stem cells and the fungus B.d. chytrid.

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Chemotaxis of Mesenchymal Stem Cells in a Microfluidic Device

MRS Proceedings ◽

10.1557/opl.2012.1659 ◽

2012 ◽

Vol 1498 ◽

pp. 67-72

Author(s):

Ruth Choa ◽

Manav Mehta ◽

Kangwon Lee ◽

David Mooney

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Microfluidic Device ◽

Soft Lithography ◽

Center Of Mass ◽

Cell Movement ◽

Microfluidic Devices ◽

Chemokine Gradient ◽

Long Time ◽

Stable Linear

ABSTRACTAdult bone marrow derived mesenchymal stem cells (MSCs) represent an important source of cells for tissue regeneration. Control of MSC migration and homing is still unclear. The goal of this study was to identify potent chemoattractants for MSCs and characterize MSC chemotaxis using a microfluidic device as a model system and assay platform. The three chemokines compared in this study were CXCL7, CXCL12, and AMD 3100.Microfluidic devices made of polydimethysiloxane (PDMS) were fabricated by soft lithography techniques and designed to generate a stable linear chemokine gradient. Cell movements in response to the gradient were captured by timelapse photos and tracked over 24 hours. Chemokine potency was measured via several chemotaxis parameters including: velocity in the direction of interest (V), center of mass (Mend), forward migration indice (YFMI). The migratory paths of the cells were mapped onto a displacement plot and compared.The following results were measured in the direction of interest (towards higher concentrations of chemokine): For velocity, only cells exposed to CXCL12 had a statistically significant (p=.014) average velocity (V=0.19 ± 0.07 um/min) when compared to the control condition (V=0.06 ±0 .04 um/min). For the center of mass, where the displacement of cells from their starting positions were compared, again only CXCL12 (Mend= 53.9 ± 10.8 um) stimulated statistically significant (p = .013) displacement of cells compared to the control condition (Mend = 19.3 ± 16.1 um). For the forward migration index, the efficiency of cell movement was measured. Indices in both the CXCL12 (YFIM = 0.19 ± 0.08) and CXCL7 (YFIM = 0.09 ±0.03) conditions were statistically significant (p = .023 for CXCL12 and p = .035 for CXCL7) when compared with the control index (YFIM = .04 ± .02).This study demonstrated the use of microfluidic devices as a viable platform for chemotaxis studies. A stable linear chemokine gradient was maintained over a long time scale to obtain cell migration results. CXCL12 was quantitatively determined to be the most potent chemoattractant in this research; these chemoattractive properties promote its use in future developments to control MSC homing.

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The DLC-1 tumor suppressor is involved in regulating immunomodulation of human mesenchymal stem cells through interacting with the Notch1 protein

10.21203/rs.2.19213/v1 ◽

2019 ◽

Author(s):

Tao Na ◽

Kehua Zhang ◽

Bao-Zhu Yuan

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Tumor Suppressor ◽

Mutual Exclusion ◽

Human Mesenchymal Stem Cells ◽

Fine Tuning ◽

Therapeutic Effects ◽

Critical Function ◽

E3 Ligases ◽

Notch1 Signaling

Abstract Immunomodulatory activities of human mesenchymal stem cells (hMSCs) have been widely accepted as the most critical function of the cells for exerting its therapeutic effects. The activities include the inhibition by hMSCs on pro-inflammatory CD4 + -T lymphocytes, and the release of immunomodulatory molecules, like IDO1. However, the detailed mechanisms responsible for regulating the immunomodulation of hMSCs still remain largely unknown. Previously, the Notch1 protein has been demonstrated to be able to promote the immunomodulation of hMSCs through inhibiting CD4 + -Th1 lymphocyte proliferation and enhancing IDO1 expression. The present study further revealed that it was the Notch1-Hey1 axis, rather than the Notch1-Hes1 axis, that was likely responsible for mediating the immunomodulation of the Notch1 signaling. Meanwhile, following a previously proposed hypothesis to identify proteasome-regulated protein(s) for limiting the activity of the Notch1 signaling in hMSCS, the DLC-1 tumor suppressor was identified to be such a candidate protein, which was subjected to protein degradation mediated by the DDB1 and FBXW5 E3 ligases . It was further shown that the DLC-1 signaling composing of DLC-1, Rock1 and FBXW5 proteins was involved in inhibiting the immunomodulation of hMSCs. More importantly, the immunomodulation was achieved through an interaction between the DLC-1-FBXW5-Rock1 signaling and the Notch1-Hey1 signaling . In fact, the present study a novel function of DLC-1 tumor suppressor as well as proposed a new mutual exclusion mechanism likely responsible for fine-tuning the immunomodulation of hMSCs.

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The DLC-1 tumor suppressor is involved in regulating immunomodulation of human mesenchymal stem cells through interacting with the Notch1 protein

10.21203/rs.2.19213/v2 ◽

2020 ◽

Author(s):

Tao Na ◽

Kehua Zhang ◽

Bao-Zhu Yuan

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Tumor Suppressor ◽

Protein Degradation ◽

Signaling Pathway ◽

Mutual Exclusion ◽

Human Mesenchymal Stem Cells ◽

Fine Tuning ◽

Notch1 Signaling ◽

Immunomodulatory Function

Abstract Background Immunomodulatory activities of human mesenchymal stem cells (hMSCs) has been widely recognized as the most critical function of hMSCs for exerting its therapeutic effects. However, the detailed mechanisms responsible for regulating the immunomodulation of hMSCs still remain largely unknown. Previous studies revealed that the Notch1 protein exerted a pro-immunomodulatory function probably through interacting with the protein(s) subjective to proteasome-mediated protein degradation. The DLC-1 protein represents a well characterized tumor suppressor subjective to proteasome-mediated degradation. However, the detailed signaling pathway of Notch1 and the involvement of DLC-1 in regulating the immunomodulation of hMSCs have not been studied before. Methods The transfection with cDNA or siRNA into hMSCs assisted by co-culture of hMSCs with peripheral blood mononuclear cells and small molecule inhibitors of signaling proteins, followed by immunoprecipitation, Western blotting, RT-PCR, and flowcytometry, were employed to characterize the Notch1 signaling, to identify DLC-1 as a candidate proteasome-targeted protein, and to characterize DLC-1 signaling pathway and its interaction with the Notch1 signaling, in the regulation of immunomodulation of hMSCs, specifically, the inhibition of pro-inflammatory CD4+-Th1 lymphocytes, and the release of immunomodulatory molecule IDO1. Statistical analysis One-way ANOVA was utilized as a statistical tool to analyze the data presented as means ± SEM of at least three separate experiments. Results The present study revealed that the Notch1-Hey1 axis, but not the Notch1-Hes1 axis, was likely responsible for mediating the pro-immunomodulatory function of the Notch1 signaling. The DLC-1 protein was found subjective to proteasome-mediated protein degradation mediated by the DDB1 and FBXW5 E3 ligases and served as an inhibitor of the immunomodulation of hMSCs through inhibiting Rock1, but not Rock2, downstream the DLC-1 signaling. The Notch1 signaling in the Notch1-Hey1 pathway and the DLC-1 signaling in the DLC-1-Rock1-FBXW5 pathway exhibited a mutual exclusion interaction in the regulation of immunomodulation of hMSCs. Conclusions The present study uncovers a novel function of DLC-1 tumor suppressor in regulating the immunomodulation of hMSCs. It also proposes a novel mutual exclusion mechanism between the DLC-1 signaling and the Notch1 signaling that is possibly responsible for fine-tuning the immunomodulation of hMSCs with different clinical implications in hMSCs therapy.

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Exosomal microRNAs derived from mesenchymal stem cells: cell-to-cell messages

Cell Communication and Signaling ◽

10.1186/s12964-020-00650-6 ◽

2020 ◽

Vol 18 (1) ◽

Cited By ~ 1

Author(s):

Kasra Asgarpour ◽

Zahra Shojaei ◽

Fatemeh Amiri ◽

Jafar Ai ◽

Maryam Mahjoubin-Tehran ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Tissue Regeneration ◽

Eukaryotic Cells ◽

Release Mechanism ◽

Immunomodulatory Effects ◽

Migration Ability ◽

Exosomal Mirnas ◽

Non Coding Rnas

Abstract Exosomes are extracellular vesicles characterized by their size, source, release mechanism and contents. MicroRNAs (miRNAs) are single stranded non-coding RNAs transcribed from DNA. Exosomes and miRNAs are widespread in eukaryotic cells, especially in mesenchymal stem cells (MSCs). MSCs are used for tissue regeneration, and also exert paracrine, anti-inflammatory and immunomodulatory effects. However, the use of MSCs is controversial, especially in the presence or after the remission of a tumor, due to their secretion of growth factors and their migration ability. Instead of intact MSCs, MSC-derived compartments or substances could be used as practical tools for diagnosis, follow up, management and monitoring of diseases. Herein, we discuss some aspects of exosomal miRNAs derived from MSCs in the progression, diagnosis and treatment of various diseases.

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Fine-Tuning Reception in the Bone: PPARγand Company

PPAR Research ◽

10.1155/ppar/2006/52950 ◽

2006 ◽

Vol 2006 ◽

pp. 1-7 ◽

Cited By ~ 3

Author(s):

Z. Elizabeth Floyd ◽

Sanjin Zvonic ◽

Mark E. Nuttall ◽

Jeffrey M. Gimble

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Hormone Receptors ◽

Oxygen Sensing ◽

Fine Tuning ◽

Nuclear Hormone Receptors ◽

Bone Marrow Stroma ◽

Factors Influencing ◽

Marrow Stroma

PPARγplays a central role in the formation of fat. Regulation of PPARγactivity depends on numerous factors ranging from dietary ligands to nuclear hormone coactivators and corepressors to oxygen-sensing mechanisms. In addition, the interplay of PPARγwith other nuclear hormone receptors has implications for the balance between adipogenesis and osteogenesis in mesenchymal stem cells of the bone marrow stroma. This review will explore a range of factors influencing PPARγactivity and how these interactions may affect osteogenesis.

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