after a cell is ' born ' , it migrates to its final destination , where it then changes its shape to assume its final role . very often , this involves the formation of cellular processes , many of which have specific shapes and functions that are characteristic to the individual cell types . this process outgrowth and other changes in morphology are supported internally by a sturdy network of specialized structural proteins that form the cytoskeleton . in addition , the surrounding extracellular environment , the extra - cellular matrix ( ecm ) , mediates the changes in cell shape through its mechanical properties . the role of the ecm becomes particularly apparent when adherent cells ( cells that are part of a tissue ) are compared with non - adherent cells ( cells that are floating freely within a liquid , such as blood ) . although most adherent cells have a very particular shape , non - adherent cell types are usually rounded but change shape when they attach to surrounding tissue , suggesting that adherent cells can sense and respond to mechanical signals from the ecm . these mechanosensory properties are mediated by special adhesion sites , where the ecm binds to a family of receptor proteins within the cell membrane . binding of ecm ligands to integrins , with the associated varying degrees of mechanical strain or stretch , promotes the recruitment and linkage of part of the cytoskeleton , the actomyosin network , to intracellular integrin domains and thus anchors this network at the lipid membrane . the actomyosin network consists of two major components , actin filaments and myosin molecules , which can slide along each other , creating an intracellular contractile force ( figure 1a ) . the relationship between this intracellular force and the strength of cell adhesion ( the extracellular force ) could then simply regulate shape such that stronger external forces would pull the cellular membrane outwards , whereas stronger internal forces would maintain a rounded shape . cells bind ecm components through integrin receptors ( represented by  and  subunits ) , thus increasing extracellular adhesion . integrin activation then triggers signaling cascades involving fyn kinase , which inhibits rhoa , thus activating rock and myosin iib . activated myosin iib interacts with actin filaments and creates strong intracellular contractions , which in turn enhances extracellular attachment and possibly mediates cell differentiation . ecm and cytosol color schemes represent the force intensity generated by these molecular events , gray being weakest and red being strongest . optimal myelination conditions require a balance between extracellular forces mediated by matrix rigidity and intracellular forces based on actomyosin contractions ( diagonal arrow ) . a softer matrix inhibits cell differentiation and myelination ( shift to the left ) , which can be counteracted by myosin iib inhibition ( cells return to being balanced ) . gliosis , as it occurs in ms , might represent a more rigid matrix ( shift to the right ) , which would require stronger contractile forces to counteract first , recent findings have emphasized the importance of functional actomyosin contractile mechanisms for the regulation of a wide range of cell properties , including tissue formation , cell migration and cell differentiation . second , in contradiction to this simple model , low contractile forces generally yield membrane - rich , bulgy cell types , whereas strong contractions lead to the formation of highly structured cell shapes . finally , different cell types reportedly have different ecm rigidity preferences for the induction of their particular shape . all this suggests that cellular shapes are determined by a precisely regulated interplay of intracellular contractile forces and extra - cellular attachment . a particularly striking example of this interplay is the neural cell lineage , which gives rise to neurons , astrocytes and oligodendrocytes in the central nervous system ( cns ) . however , neurons , which are generated first , prefer relatively soft surfaces for elaboration and branching of axons and dendrites . these softer substrates possibly correspond to the environmental conditions at the time of initial pathfinding of neuronal processes . in contrast , in recently published work in bmc cell biology , simons and colleagues show that the myelin - forming oligodendrocytes that develop later form their highly processed morphology and extensive myelin sheets best on more rigid surfaces . this seems logical if we take a closer look at the developmental context of the formation of the insulating myelin sheath around axons . once the migratory oligodendrocyte precursor cells ( opcs ) have reached their destination and start to establish contact with an axon , their processes change from exploring the unstructured extracellular environment of the presumptive myelinated tract , as required for migration , to the establishment of close contact with the highly structured ( and therefore probably more rigid ) surface of the axon , initiating the process of wrapping it with membranous sheets that will eventually become the compact myelin sheath . an increase in intracellular force would therefore be necessary to enable the opposing forces to be matched and promote the next stage of oligodendrocyte development the findings of simons and co - workers   also provide information about these intracellular mechanisms . investigation of the role of intracellular contractility in differentiation and myelination identified myosin iib , one of the major components of the actomyosin cytoskeleton , as a central player in generating intracellular force . in cell culture experiments , softer surfaces inhibit process outgrowth , as would be predicted if oligodendrocyte differentiation is normally associated with increased levels of intracellular force to match the increased rigidity of the axons . this effect can be overcome by pharmacological inhibition of myosin iib , which will reduce intracellular contractions and thus better match intracellular force with the lower extracellular attachment efficacy provided by less rigid substrate ( figure 1b ) . the first is that they offer a clue as to how one might explain the rather surprising reported effects of myosin iib inhibition on myelination in culture . .   showed that myosin iib inhibition in a neuron - oligo - dendrocyte co - culture system significantly enhanced the formation of the myelin sheath , a change that resulted from individual oligodendrocytes forming more wrapping processes than cells in untreated control cultures . in complete contrast , inhibition of myosin iib in co - cultures of schwann cells ( the myelinating cells of the peripheral nervous system ) with neurons inhibited myelination , and cellular morphology was characterized by aberrant process outgrowth . in short , while schwann cells react as would be predicted , oligodendrocytes exhibit a behavior that contradicts the conclusions obtained from previous experiments . this might reflect important differences in the biology of the schwann cell and the oligodendrocyte , in particular in respect to their adjustment to in vitro conditions : the extracellular forces on the schwann cell appear to be similar in culture and in vivo , whereas the extracellular forces on oligodendrocytes in culture are potentially weaker than in vivo . the presence of a basal lamina on the non - axonal side of the schwann cell but not the oligodendrocyte both in vitro and in vivo might be one means of retaining such an extracellular force . the second , and more important , reason for interest in the findings of simons and colleagues   is that they offer explanations as to why remyelination might fail in the demyelinating disease multiple sclerosis ( ms ) . in ms , unknown molecular triggers induce an inflammatory reaction in the brain leading to an invasion and activation of immune cells ( b and t lymphocytes and macrophages ) and/or the produc tion of antibodies directed against myelin components . remyelination does occur in the early stages of the disease as intrinsic mechanisms mediate the recruitment of opcs , which then align with the denuded axon and regenerate the sheath . however , this repair mechanism eventually fails , for as - yet unknown reasons . an implication of the results of simons and colleagues   is that increased rigidity in the scarred brain may play a role by unbalancing the intracellular and extracellular forces and inhibiting oligodendrocyte differentiation ( figure 1b ) . astrocytes , the third cell type derived from the neural lineage , provide nutrients to neurons and oligodendrocytes , give biochemical support to the cells forming the blood - brain barrier and , in particular , mediate the repair and scarring processes in the cns following traumatic injuries . they respond to pathological insults , including inflammation and demyelination , with so - called reactive gliosis . on a cellular level , this is characterized by an upregulation of intermediate filament proteins , leading to the formation of a prominent intermediate filament network directly underneath the plasma membrane , rendering the cellular texture more fibrous . furthermore , pronounced changes in expression of adhesion molecule genes have been described , which would result in an altered ecm composition compared with that of initial myelination . in demyelinated plaques , reactive astrocytes are the most abundant cellular component , and astroglial scars have been described as being more rigid than their surrounding tissue . these properties might alter force - sensing integrin function in the oligodendrocyte , unbalancing the cellular forces and inhibiting remyelination . the main implications of the findings of simons and colleagues   are , therefore , that a particular balance of extracellular adhesion , matrix rigidity and intracellular contractile forces mediated by the oligodendrocyte actomyosin cytoskeleton is required for successful myelination and remyelination . one interesting prediction implied by these data is that extracellular cues that do not in themselves alter rigidity , but that do change the activity of signaling molecules regulating intracellular force , could also inhibit remyelination . as discussed above , the predominant pathway involved in the signaling mecha nisms underlying mechanosensing and mechanotransduction is binding of ecm ligands to integrin receptors in the membrane . the activation of integrins by mechanical forces results in the recruitment of intracellular mediators that signal through a pathway involving rhoa and its downstream effector rock to activate force - generating myosin ii ( figure 1a ) . the observation that the inhibitory effects of myelin debris on opc differentiation , myelination and remyelination are mediated by rhoa - rock signaling   is consistent with this hypothesis . subsequent pharmacological disruption of the rock pathway , inhibiting myosin iib and thus actomyosin contractility , was able to enhance oligodendrocyte differentiation . clearly , the signaling molecules that regulate intracellular force now provide an intriguing source of candidates for drug discovery programs aimed at enhancing remyelination ( figure 1b ) .
a recent report in bmc cell biology examines how the balance of extracellular forces and intracellular contractions regulate the shape changes required for oligodendrocyte myelination . 
 a failure of remyelination such as seen in multiple sclerosis could be caused by loss of this balance.see related research article