Faculty Opinions recommendation of Membrane Tension Gates ERK-Mediated Regulation of Pluripotent Cell Fate.

Kindlin-2 is a multidomain intracellular protein that can be recruited to β-integrin domains to activate signaling, initiate transcriptional programs, and bind to E-cadherin. To explore its involvement in cell fate decisions in mesenchymal cells, we studied the effects of Kindlin-2 modification (overexpression/knockdown) in induced pluripotent cell-derived mesenchymal stromal cells (iPSC-MSCs). Kindlin-2 overexpression resulted in increased proliferation and reduced apoptosis of iPSC-MSCs, as well as inhibition of their differentiation towards osteocytes, adipocytes, and chondrocytes. In contrast, siRNA-mediated Kindlin-2 knockdown induced increased apoptosis and increased differentiation response in iPSC-MSCs. The ability of iPSC-MSCs to adhere to VCAM-1/SDF-1α under shear stress and to migrate in a wound scratch assay was significantly increased after Kindlin-2 overexpression. In contrast, inhibition of mixed lymphocyte reaction (MLR) was generally independent of Kindlin-2 modulation in iPSC-MSCs, except for decreased production of interleukin-2 (IL-2) after Kindlin-2 overexpression in iPS-MSCs. Thus, Kindlin-2 upregulates survival, proliferation, stemness, and migration potential in iPSC-MSCs and may therefore be beneficial in optimizing performance of iPSC-MSC in therapies.

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Endogenous fluctuations of OCT 4 and SOX 2 bias pluripotent cell fate decisions

Molecular Systems Biology ◽

10.15252/msb.20199002 ◽

2019 ◽

Vol 15 (9) ◽

Cited By ~ 10

Author(s):

Daniel Strebinger ◽

Cédric Deluz ◽

Elias T Friman ◽

Subashika Govindan ◽

Andrea B Alber ◽

...

Keyword(s):

Cell Fate ◽

Pluripotent Cell ◽

Endogenous Fluctuations ◽

Cell Fate Decisions

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Membrane tension mediated mechanotransduction drives fate choice in embryonic stem cells

10.1101/798959 ◽

2019 ◽

Cited By ~ 9

Author(s):

Henry De Belly ◽

Philip H. Jones ◽

Ewa K. Paluch ◽

Kevin J. Chalut

Keyword(s):

Cell Fate ◽

Cell Mechanics ◽

Cell Shape ◽

Es Cells ◽

Embryonic Stem ◽

Beta Catenin ◽

Membrane Tension ◽

Es Cell ◽

Early Differentiation ◽

Fgf Signalling

Changes in cell shape and mechanics frequently accompany cell fate transitions. Yet how mechanics affects the regulatory path-ways controlling cell fate is poorly understood. To probe the interplay between shape, mechanics and fate, we used embryonic stem (ES) cells, which spread as they undergo early differentiation. We found that this spreading is regulated by a beta-catenin mediated decrease in plasma membrane tension. Strikingly, preventing the membrane tension decrease obstructs early differentiation of ES cells. We further find that blocking the decrease in membrane tension inhibits endocytosis of FGF signalling components, which direct the exit from the ES cell state. The early differentiation defects we observed can be rescued by increasing Rab5a-facilitated endocytosis. Thus, we show that a mechanically-triggered increase in endocytosis regulates fate transitions. Our findings are of fundamental importance for understanding how cell mechanics regulates biochemical signaling, and therefore cell fate.

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Centrosome Aurora A gradient ensures single polarity axis in C. elegans embryos

Biochemical Society Transactions ◽

10.1042/bst20200298 ◽

2020 ◽

Vol 48 (3) ◽

pp. 1243-1253 ◽

Cited By ~ 1

Author(s):

Sukriti Kapoor ◽

Sachin Kotak

Keyword(s):

Symmetry Breaking ◽

Cell Fate ◽

Cell Cortex ◽

Axis Formation ◽

Aurora A Kinase ◽

Aurora A ◽

C Elegans ◽

Cell Embryo ◽

Polarity Establishment

Cellular asymmetries are vital for generating cell fate diversity during development and in stem cells. In the newly fertilized Caenorhabditis elegans embryo, centrosomes are responsible for polarity establishment, i.e. anterior–posterior body axis formation. The signal for polarity originates from the centrosomes and is transmitted to the cell cortex, where it disassembles the actomyosin network. This event leads to symmetry breaking and the establishment of distinct domains of evolutionarily conserved PAR proteins. However, the identity of an essential component that localizes to the centrosomes and promotes symmetry breaking was unknown. Recent work has uncovered that the loss of Aurora A kinase (AIR-1 in C. elegans and hereafter referred to as Aurora A) in the one-cell embryo disrupts stereotypical actomyosin-based cortical flows that occur at the time of polarity establishment. This misregulation of actomyosin flow dynamics results in the occurrence of two polarity axes. Notably, the role of Aurora A in ensuring a single polarity axis is independent of its well-established function in centrosome maturation. The mechanism by which Aurora A directs symmetry breaking is likely through direct regulation of Rho-dependent contractility. In this mini-review, we will discuss the unconventional role of Aurora A kinase in polarity establishment in C. elegans embryos and propose a refined model of centrosome-dependent symmetry breaking.

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Centromere assembly and non-random sister chromatid segregation in stem cells

Essays in Biochemistry ◽

10.1042/ebc20190066 ◽

2020 ◽

Vol 64 (2) ◽

pp. 223-232 ◽

Cited By ~ 1

Author(s):

Ben L. Carty ◽

Elaine M. Dunleavy

Keyword(s):

Stem Cells ◽

Cell Division ◽

Cell Fate ◽

Sister Chromatid ◽

Asymmetric Cell Division ◽

Protein A ◽

Germline Stem Cells ◽

Sister Chromatids ◽

Centromere Protein A ◽

Oocyte Meiosis

Abstract Asymmetric cell division (ACD) produces daughter cells with separate distinct cell fates and is critical for the development and regulation of multicellular organisms. Epigenetic mechanisms are key players in cell fate determination. Centromeres, epigenetically specified loci defined by the presence of the histone H3-variant, centromere protein A (CENP-A), are essential for chromosome segregation at cell division. ACDs in stem cells and in oocyte meiosis have been proposed to be reliant on centromere integrity for the regulation of the non-random segregation of chromosomes. It has recently been shown that CENP-A is asymmetrically distributed between the centromeres of sister chromatids in male and female Drosophila germline stem cells (GSCs), with more CENP-A on sister chromatids to be segregated to the GSC. This imbalance in centromere strength correlates with the temporal and asymmetric assembly of the mitotic spindle and potentially orientates the cell to allow for biased sister chromatid retention in stem cells. In this essay, we discuss the recent evidence for asymmetric sister centromeres in stem cells. Thereafter, we discuss mechanistic avenues to establish this sister centromere asymmetry and how it ultimately might influence cell fate.

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