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Concise Review: Plasma and Nuclear Membranes Convey Mechanical Information to Regulate Mesenchymal Stem Cell Lineage

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Concise Review: Plasma and Nuclear Membranes Convey Mechanical Information to Regulate Mesenchymal Stem Cell Lineage TISSUE-SPECIFIC STEM CELLS Concise Review: Plasma and Nuclear Membranes Convey Mechanical Information to Regulate Mesenchymal Stem Cell Lineage a b a b GUNES UZER, ROBYN K. FUCHS, JANET RUBIN, WILLIAM R. THOMPSON Key Words. LINC • Emerin • Nesprin • Lamin • Vibration • Exercise • Mesenchymal stem cell aDepartment of Medicine, ABSTRACT University of North Carolina, Numerous factors including chemical, hormonal, spatial, and physical cues determine stem cell Chapel Hill, North Carolina, fate. While the regulation of stem cell differentiation by soluble factors is well-characterized, USA; bSchool of Health and the role of mechanical force in the determination of lineage fate is just beginning to be under- Rehabilitation Sciences, stood. Investigation of the role of force on cell function has largely focused on “outside-in” sig- Department of Physical naling, initiated at the plasma membrane. When interfaced with the extracellular matrix, the Therapy, Indiana University, Indianapolis, Indiana, USA cell uses integral membrane proteins, such as those found in focal adhesion complexes to trans- late force into biochemical signals. Akin to these outside-in connections, the internal cytoskele- Correspondence: William R. ton is physically linked to the nucleus, via proteins that span the nuclear membrane. Although Thompson, D.P.T., Ph.D., 1140 structurally and biochemically distinct, these two forms of mechanical coupling influence stem W. Michigan Street, cell lineage fate and, when disrupted, often lead to disease. Here we provide an overview of Indianapolis, Indiana 46202, how mechanical coupling occurs at the plasma and nuclear membranes. We also discuss the USA. Telephone: 317-278-9619; role of force on stem cell differentiation, with focus on the biochemical signals generated at Fax: 317-278-1876; the cell membrane and the nucleus, and how those signals influence various diseases. While e-mail: [email protected] the interaction of stem cells with their physical environment and how they respond to force is Received October 7, 2015; complex, an understanding of the mechanical regulation of these cells is critical in the design of accepted for publication novel therapeutics to combat diseases associated with aging, cancer, and osteoporosis. STEM December 29, 2015; first CELLS 2016;34:1455–1463 published online in STEM CELLS EXPRESS February 17, 2016. SIGNIFICANCE STATEMENT VC AlphaMed Press 1066-5099/2016/$30.00/0 This concise review details the ability of stem cells to regulate their lineage allocation based on mechanical forces exerted upon them. The mechanical qualities of both the external environ- http://dx.doi.org/ ment (the extracellular matrix) and the internal cytoskeleton of stem cells alter how they 10.1002/stem.2342 respond. Additionally, forces are translated into biochemical signals using different molecular Available online without machinery at the plasma membrane and nuclear membrane. These distinctions have been out- subscription through the open lined in this paper and the consequent diseases have been described. access option. to perceive and transmit mechanical force INTRODUCTION intracellularly [3]. Biological systems are fine-tuned to sense, For bone marrow mesenchymal stem cells respond, and adapt to physical stimuli [1]. In (MSCs), a more structured cytoskeleton leads the case of stem cells, the external physical to differentiation into lineages making up tis- environment guides stem cell fate decisions sues with greater mechanical competence (i.e., [2]. As such, stem cells, as a prototype of mul- bone, cartilage). It is important to note that tiple descendent lineages, possess mechano- MSCs form heterogeneous populations, distrib- sensory machinery to translate mechanical uted along a dynamic differentiation spectrum. signals into biochemical responses. Further- While the question of whether the contribu- more, cells adapt and respond to physical tion of MSCs to different lineages stem from forces by remodeling their internal physical direct fate switching or a modular responsive- structures to regulate interactions with the ness of different subpopulations remains unre- external physical environment. Application of solved, it is reasonable to expect that up until mechanical force initiates signaling cascades at some point the fate of MSC populations the plasma membrane leading to the genera- remain plastic, rendering them susceptible to tion and remodeling of filamentous actin incoming mechanical signals [4]. In this way, stress fibers, which enhance the cell’s ability both “outside-in” and “inside-out” force STEM CELLS 2016;34:1455–1463 www.StemCells.com VC AlphaMed Press 2016 1456 Role of Nuclear Envelope on MSC Lineage signaling determine MSC lineage fate. In the former, the stiff- CELLULAR ARCHITECTURE INFLUENCES MSC DIFFERENTIATION ness of the substrate [5], or application of external mechani- cal force [6], induces intracellular effects. In inside-out MSCs are abundantly found within the bone marrow and adi- signaling, scaffolding of intracellular proteins reinforces pose depots and have the ability to develop into mesenchy- integrin-based attachments [7]. mal tissues including bone, cartilage, fat, and muscle [13]. At the interface between the basal substrate and adjacent MSC lineage fate is strongly dependent upon the context of cells, the plasma membrane uses specific structural proteins the physical environment, both topographical and mechanical to transduce force into biochemical signals. These structural qualities of the surrounding matrix, as well as the dynamic proteins gather together to form focal adhesions (FAs), which mechanical environment modulate the allocation of MSCs [1]. span the cell membrane and connect the extracellular matrix Cellular structure is largely determined by its cytoskeleton, to the actin cytoskeleton. FAs also serve as hubs for signaling which is a dynamic structure primarily composed of three molecules to congregate, where the combination of force types of proteins: microfilaments (actin), microtubules (tubu- transmission and signal transduction result in further cytos- lin), and intermediate filaments [14]. While actin fibers and keletal remodeling [8]. Recent work also identifies the microtubules are made up of one type of monomer (actin nucleus, and its membrane, as mechanosensory organelles, and tubulin, respectively), intermediate filaments have a wide where anchoring to the cytoskeleton via the LINC (Linker of variety of different monomers that form the larger filamen- Nucleoskeleton and Cytoskeleton) complex enables transmis- tous structures. Hundreds of other proteins associate with the sion of mechanical force between the nucleus, the cytoskele- cytoskeleton including crosslinkers, molecular motors, and sig- ton outward to the external microenvironment [9]. In this naling effectors. Cytoskeletal fibers, especially actin filaments, are acutely sensitive to both chemical and physical modula- way, mechanical signals have the potential to further regulate tion. For instance, application of mechanical force enables connections between the nucleus and the cell cytoskeleton, globular actin monomers (G-actin) to aggregate and form generating another level whereby mechanical input can con- structured filamentous fibers (F-actin). Formation of actin trol cell behavior. Thus, while it has become accepted that fibers, from monomers, is controlled in large part by Rho genetic elements within the nucleus respond to mechanical GTPases including RhoA, where exchange of GTP induces acti- challenges indirectly through their transduction into interme- vation of RhoA, leading to actin stress fiber polymerization diary biochemical cascades [1], it has only recently been con- [15]. Thus, the structure of the cytoskeleton is extremely sidered that applied forces might also directly alter dynamic, enabling modification of cellular shape, intracellular chromosomal conformations, thus influencing the accessibility signaling events, and thus cellular behavior and phenotype. of genetic information for binding of transcriptional enhancers Mechanically, cell structure undergoes a continual balance or repressors [10]. of inner and outer forces which allow cellular components to As mechanical signals are critical for directing cellular experience both compression and tension, a process summed responses, dysfunction of the mechanosensory machinery can in the concept of tensegrity [16]. The tensegrity structure acts lead to disease. One such example at the level of nuclear as a global sensory mechanism for mechanical cues, allowing force control is Hutchinson-Gilford progeria syndrome, which for rapid structural responses to static and dynamic mechani- manifests symptoms of aging at a very early age. This condi- cal loads [17]. Such structural responses are mediated through tion arises due to due a mutation in Lamin A/C, a structural the actin cytoskeleton, where FA connections facilitate the protein at the inner nuclear membrane [11]. Thus, unlike dis- tensegrity balance, connecting the inner cytoskeleton with the eases of “accelerated aging” including Werner syndrome, matrix outside the cell. which are caused by defective DNA repair, this “laminopathy” Early studies showed that increased matrix stiffness results from inadequate mechanical support and abnormal enhanced the size of FA sites in fibroblasts, while softer sub- nuclear structure [12]. Thus, the structural relationship of strates resulted in smaller, more mobile FAs [18]. As FAs are Lamin A/C and other nuclear membrane scaffolding proteins the
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