Quantitative parsing of cell multi-tasking in wound repair and tissue morphogenesis.

Wound healing is a complex process ofcell colonization, matrix deposition,and remodeling, requiring multiple cellfunctions to act in coordinated manner.Focusing on dermal tissue regenerationas a prominent example, a relativelysimpliﬁedviewcanbeproffered:properhealing requires ﬁbroblast migrationinto the wound, synthesis and secretionof extracellular matrix components,and active contraction-based reorgan-ization of the matrix around the occu-pying cells. These actions occur in anoverlapping but sequenced order inthe face of a multitude of external cuesfrom a changing environment. Furthercomplicating this situation is the factthat these stages of wound repair occurasynchronously across a larger, healingwound. The ways by which thesediverse cell behaviors—locomotion,matrix production, and tissue remod-eling—interact to ultimately yield ei-therpropertissuephysiologyorvariouskinds of pathology remain poorly un-derstood,even to the issueof the natureof the cells involved in any or all ofthese functions (Tomasek et al., 2002).For investigators in the biophysicscommunity, an especially germanefacet of this complicated phenomenonis the relationship between cell loco-motion and matrix reorganization,particularly since the matrix reorgani-zation requires matrix contraction. Attheir core both the cellular immigrationand the matrix contraction arise fromintracellular cytoskeletal force genera-tion transmitted to the extracellularmatrix via highly regulated cell/matrixadhesion sites (Tamariz and Grinnell,2002). Controversy has existed in thewound healing and tissue morphogen-esis ﬁeld about whether compaction ofextracellular matrix derives, on the onehand, from migratingcells asthey exerttraction during locomotion, or, on theother hand, by nonmigrating cells con-verting their intracellular contractileforce into traction. In fact, ﬁbroblastmotility can be converted into matrixcompaction by inhibiting molecularmechanisms involved in regulated re-leaseofcell/matrixadhesionsoperatingin migration (Allen et al., 2002). Thus,it is exceedingly difﬁcult to parsecontributions of underlying molecularmechanisms to overall wound healingand tissue morphogenesis in terms ofactive cell migration versus cell motil-ity-derivedmatrix deformations.It maysimply be that they are part-and-parcelaspects of the same underlying motilitymachinery modulated by external sig-nals that abrogate key events. It is,therefore, crucial to gain this capabilityfor analyzing the ‘‘multitasking’’ cellscan accomplish with their force gen-eration and transmission regulation inorder to test hypotheses that can lead toimproved molecular therapeutics forwound regeneration and particularlywound strengthening.A major advance toward this impor-tant goal is provided by the new workby Shreiber et al. in this issue of theBiophysical Journal (Shreiber et al.,2003), by simultaneous quantitativemeasurement of cell migration andmatrixdeformationforﬁbroblastswith-in three-dimensional collagen gels asfunctionsoftimeoveraperiodofhours.These gels are cylindrical andanchoredat their axial ends, so that matrix de-formationoccurs in the radial direction.The automated microscopy and imageanalysis technology needed for thiscapability had been demonstrated pre-viously by the Tranquillo laboratoryat Minnesota in recent years, but thecrucial extension here determination oftime-varying characteristics of thesecellbehavioralfunctionsconcomitantlyenabling analysis of dynamic changesin locomotion and remodeling reﬂect-ing progressions of the extracellularcontext (e.g., matrix composition andcompliance) as well as cellular pheno-typic properties (due to gene expres-sion modulation, for instance).In this new study, the Tranquillogroup compared dynamic cell migra-tion and matrix compaction propertiesof human foreskin ﬁbroblasts (HFFs)and rat dermal ﬁbroblasts (RDFs) inresponse to serum. Both cell typesgenerally showed increasing values ofthe random migration coefﬁcient,l (analogous to a molecular diffusioncoefﬁcient), as time progressed, whilethevaluesofthecelltractioncoefﬁcent,s