Cell shape, cytoskeletal tension, and rhoa regulate stem cell lineage commitment
TL;DR: It is demonstrated that cell shape regulates commitment of human mesenchymal stem cells to adipocyte or osteoblast fate and mechanical cues experienced in developmental and adult contexts, embodied by cell shape, cytoskeletal tension, and RhoA signaling, are integral to the commitment of stem cell fate.
About: This article is published in Developmental Cell.The article was published on 2004-04-01 and is currently open access. It has received 3995 citations till now. The article focuses on the topics: RHOA & Stem cell.
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TL;DR: Naive mesenchymal stem cells are shown here to specify lineage and commit to phenotypes with extreme sensitivity to tissue-level elasticity, consistent with the elasticity-insensitive commitment of differentiated cell types.
12,204 citations
Cites background or result from "Cell shape, cytoskeletal tension, a..."
...Similar results as above are found with a standard osteoblast induction media (OIM), which is known to promote cytoskeletal rearrangement and alkaline phosphatase production (Jaiswal et al., 1997; McBeath et al., 2004)....
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...Lineage specification of naive stem cells induced by soluble stimuli has been well described (Gang et al., 2004; Jaiswal et al., 1997; McBeath et al., 2004; Pittenger et al., 1999), but the results here report a strong and previously undocumented influence of microenvironment stiffness on stem cell…...
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...(McBeath et al., 2004; Wang et al., 2002)....
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...Myosins in MSCs Couple Expression to Matrix Stiffness and Reveal a Key Role for NMM IIs Forces generated and/or imposed on the cell’s actin cytoskeleton have been postulated to influence differentiation (Engler et al., 2004a; Hinz et al., 2001; McBeath et al., 2004), but no past reports have hinted at strong, tissuedirected feedback of microenvironment elasticity on myosin expression or stem cell lineage specification....
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...Lineage specification of naive stem cells induced by soluble stimuli has been well described (Gang et al., 2004; Jaiswal et al., 1997; McBeath et al., 2004; Pittenger et al., 1999), but the results here report a strong and previously undocumented influence of microenvironment stiffness on stem cell specification....
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TL;DR: YAP/TAZ are identified as sensors and mediators of mechanical cues instructed by the cellular microenvironment and are functionally required for differentiation of mesenchymal stem cells induced by ECM stiffness and for survival of endothelial cells regulated by cell geometry.
Abstract: Cells perceive their microenvironment not only through soluble signals but also through physical and mechanical cues, such as extracellular matrix (ECM) stiffness or confined adhesiveness. By mechanotransduction systems, cells translate these stimuli into biochemical signals controlling multiple aspects of cell behaviour, including growth, differentiation and cancer malignant progression, but how rigidity mechanosensing is ultimately linked to activity of nuclear transcription factors remains poorly understood. Here we report the identification of the Yorkie-homologues YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif, also known as WWTR1) as nuclear relays of mechanical signals exerted by ECM rigidity and cell shape. This regulation requires Rho GTPase activity and tension of the actomyosin cytoskeleton, but is independent of the Hippo/LATS cascade. Crucially, YAP/TAZ are functionally required for differentiation of mesenchymal stem cells induced by ECM stiffness and for survival of endothelial cells regulated by cell geometry; conversely, expression of activated YAP overrules physical constraints in dictating cell behaviour. These findings identify YAP/TAZ as sensors and mediators of mechanical cues instructed by the cellular microenvironment.
4,120 citations
TL;DR: Multifaceted technologies are increasingly required to produce and interrogate cells ex vivo, to build predictive models, and, ultimately, to enhance stem cell integration in vivo for therapeutic benefit.
Abstract: Stem cell fate is influenced by a number of factors and interactions that require robust control for safe and effective regeneration of functional tissue. Coordinated interactions with soluble factors, other cells, and extracellular matrices define a local biochemical and mechanical niche with complex and dynamic regulation that stem cells sense. Decellularized tissue matrices and synthetic polymer niches are being used in the clinic, and they are also beginning to clarify fundamental aspects of how stem cells contribute to homeostasis and repair, for example, at sites of fibrosis. Multifaceted technologies are increasingly required to produce and interrogate cells ex vivo, to build predictive models, and, ultimately, to enhance stem cell integration in vivo for therapeutic benefit.
2,446 citations
TL;DR: Interest in adipogenesis has increased markedly over the past few years with emphasis on the intersection between extracellular signals and the transcriptional cascade that regulates adipocyte differentiation.
Abstract: Improved knowledge of all aspects of adipose biology will be required to counter the burgeoning epidemic of obesity. Interest in adipogenesis has increased markedly over the past few years with emphasis on the intersection between extracellular signals and the transcriptional cascade that regulates adipocyte differentiation. Many different events contribute to the commitment of a mesenchymal stem cell to the adipocyte lineage including the coordination of a complex network of transcription factors, cofactors and signalling intermediates from numerous pathways.
2,363 citations
TL;DR: The extracellular matrix (ECM), a complex network of macromolecules with distinctive physical, biochemical, and biomechanical properties, is commonly deregulated and becomes disorganized in diseases such as cancer.
Abstract: The local microenvironment, or niche, of a cancer cell plays important roles in cancer development. A major component of the niche is the extracellular matrix (ECM), a complex network of macromolecules with distinctive physical, biochemical, and biomechanical properties. Although tightly controlled during embryonic development and organ homeostasis, the ECM is commonly deregulated and becomes disorganized in diseases such as cancer. Abnormal ECM affects cancer progression by directly promoting cellular transformation and metastasis. Importantly, however, ECM anomalies also deregulate behavior of stromal cells, facilitate tumor-associated angiogenesis and inflammation, and thus lead to generation of a tumorigenic microenvironment. Understanding how ECM composition and topography are maintained and how their deregulation influences cancer progression may help develop new therapeutic interventions by targeting the tumor niche.
2,353 citations
References
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TL;DR: Adult stem cells isolated from marrow aspirates of volunteer donors could be induced to differentiate exclusively into the adipocytic, chondrocytic, or osteocytic lineages.
Abstract: Human mesenchymal stem cells are thought to be multipotent cells, which are present in adult marrow, that can replicate as undifferentiated cells and that have the potential to differentiate to lineages of mesenchymal tissues, including bone, cartilage, fat, tendon, muscle, and marrow stroma. Cells that have the characteristics of human mesenchymal stem cells were isolated from marrow aspirates of volunteer donors. These cells displayed a stable phenotype and remained as a monolayer in vitro. These adult stem cells could be induced to differentiate exclusively into the adipocytic, chondrocytic, or osteocytic lineages. Individual stem cells were identified that, when expanded to colonies, retained their multilineage potential.
20,479 citations
"Cell shape, cytoskeletal tension, a..." refers background in this paper
...This RhoAcombinations (Pittenger et al., 1999, 2002)....
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...…process, as the While differentiation may cause changes in cell shape, ability of these cells to become adipocytes and osteoblasts from multipotent mesenchymal precursor cells has been well documented (Friedenstein, 1976; Caplan,*Correspondence: cchen@bme.jhu.edu 1991; Pittenger et al., 1999)....
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...However, the RhoA-mediated capable of differentiation to multiple lineages importantadipogenesis or osteogenesis was conditional on a to connective tissue (Pittenger et al., 1999)....
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TL;DR: The study of mesenchymal stem cells, whether isolated from embryos or adults, provides the basis for the emergence of a new therapeutic technology of self‐cell repair.
4,861 citations
TL;DR: Human and bovine capillary endothelial cells were switched from growth to apoptosis by using micropatterned substrates that contained extracellular matrix-coated adhesive islands of decreasing size to progressively restrict cell extension.
Abstract: Human and bovine capillary endothelial cells were switched from growth to apoptosis by using micropatterned substrates that contained extracellular matrix-coated adhesive islands of decreasing size to progressively restrict cell extension. Cell spreading also was varied while maintaining the total cell-matrix contact area constant by changing the spacing between multiple focal adhesion-sized islands. Cell shape was found to govern whether individual cells grow or die, regardless of the type of matrix protein or antibody to integrin used to mediate adhesion. Local geometric control of cell growth and viability may therefore represent a fundamental mechanism for developmental regulation within the tissue microenvironment.
4,641 citations
TL;DR: Rho GTPases are molecular switches that control a wide variety of signal transduction pathways in all eukaryotic cells and their ability to influence cell polarity, microtubule dynamics, membrane transport pathways and transcription factor activity is probably just as significant.
Abstract: Rho GTPases are molecular switches that control a wide variety of signal transduction pathways in all eukaryotic cells. They are known principally for their pivotal role in regulating the actin cytoskeleton, but their ability to influence cell polarity, microtubule dynamics, membrane transport pathways and transcription factor activity is probably just as significant. Underlying this biological complexity is a simple biochemical idea, namely that by switching on a single GTPase, several distinct signalling pathways can be coordinately activated. With spatial and temporal activation of multiple switches factored in, it is not surprising to find Rho GTPases having such a prominent role in eukaryotic cell biology.
4,616 citations
Book•
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01 Jan 1917
TL;DR: This book is an application of some of the concepts of physical science and sundry mathematical methods to the study of organic form and is like one of Darwin's books, well-considered, patiently wrought-out, learned, and cautious.
Abstract: Introduction John Tyler Bonner VII 1. Introductory 2. On magnitude 3. The forms of cells 4. The forms of tissues, of cell-aggregates 5. On spicules and spicular skeletons 6. The equiangular spiral 7. The shapes of horns and of teeth or tusks 8. On form and mechanical efficiency 9. On the theory of transformations, or the comparison of related forms 10. Epilogue Index.
4,470 citations