MRIP Regulates the Myosin IIA Activity and DDR1 Function to Enable Collagen Tractional Remodeling.

DDR1 is a collagen adhesion-mechanoreceptor expressed in fibrotic lesions. DDR1 mediates non-muscle myosin IIA (NMIIA)-dependent collagen remodeling. We discovered that the myosin phosphatase Rho-interacting protein (MRIP), is enriched in DDR1-NMIIA adhesions on collagen. MRIP regulates RhoA- and myosin phosphatase-dependent myosin activity. We hypothesized that MRIP regulates DDR1-NMIIA interactions to enable cell migration and collagen tractional remodeling. After deletion of MRIP in ß1-integrin null cells expressing DDR1, in vitro wound closure, collagen realignment, and contraction were reduced. Cells expressing DDR1 and MRIP formed larger and more abundant DDR1 clusters on collagen than cells cultured on fibronectin or cells expressing DDR1 but null for MRIP or cells expressing a non-activating DDR1 mutant. Deletion of MRIP reduced DDR1 autophosphorylation and blocked myosin light chain-dependent contraction. Deletion of MRIP did not disrupt the association of DDR1 with NMIIA. We conclude that MRIP regulates NMIIA-dependent DDR1 cluster growth and activation. Accordingly, MRIP may provide a novel drug target for dysfunctional DDR1-related collagen tractional remodeling in fibrosis.

Haptic Glove and Platform with Gestural Control For Neuromorphic Tactile Sensory Feedback In Medical Telepresence †.

Advancements in the study of the human sense of touch are fueling the field of haptics. This is paving the way for augmenting sensory perception during object palpation in tele-surgery and reproducing the sensed information through tactile feedback. Here, we present a novel tele-palpation apparatus that enables the user to detect nodules with various distinct stiffness buried in an ad-hoc polymeric phantom. The contact force measured by the platform was encoded using a neuromorphic model and reproduced on the index fingertip of a remote user through a haptic glove embedding a piezoelectric disk. We assessed the effectiveness of this feedback in allowing nodule identification under two experimental conditions of real-time telepresence: In Line of Sight (ILS), where the platform was placed in the visible range of a user; and the more demanding Not In Line of Sight (NILS), with the platform and the user being 50 km apart. We found that the entailed percentage of identification was higher for stiffer inclusions with respect to the softer ones (average of 74% within the duration of the task), in both telepresence conditions evaluated. These promising results call for further exploration of tactile augmentation technology for telepresence in medical interventions.

Neuromorphic Vibrotactile Stimulation of Fingertips for Encoding Object Stiffness in Telepresence Sensory Substitution and Augmentation Applications.

We present a tactile telepresence system for real-time transmission of information about object stiffness to the human fingertips. Experimental tests were performed across two laboratories (Italy and Ireland). In the Italian laboratory, a mechatronic sensing platform indented different rubber samples. Information about rubber stiffness was converted into on-off events using a neuronal spiking model and sent to a vibrotactile glove in the Irish laboratory. Participants discriminated the variation of the stiffness of stimuli according to a two-alternative forced choice protocol. Stiffness discrimination was based on the variation of the temporal pattern of spikes generated during the indentation of the rubber samples. The results suggest that vibrotactile stimulation can effectively simulate surface stiffness when using neuronal spiking models to trigger vibrations in the haptic interface. Specifically, fractional variations of stiffness down to 0.67 were significantly discriminated with the developed neuromorphic haptic interface. This is a performance comparable, though slightly worse, to the threshold obtained in a benchmark experiment evaluating the same set of stimuli naturally with the own hand. Our paper presents a bioinspired method for delivering sensory feedback about object properties to human skin based on contingency-mimetic neuronal models, and can be useful for the design of high performance haptic devices.

Discoidin Domain Receptor 1 Mediates Myosin-Dependent Collagen Contraction.

Discoidin domain receptor 1 (DDR1) is a tyrosine kinase collagen adhesion receptor that mediates cell migration through association with non-muscle myosin IIA (NMIIA). Because DDR1 is implicated in cancer fibrosis, we hypothesized that DDR1 interacts with NMIIA to enable collagen compaction by traction forces. Mechanical splinting of rat dermal wounds increased DDR1 expression and collagen alignment. In periodontal ligament of DDR1 knockout mice, collagen mechanical reorganization was reduced >30%. Similarly, cultured cells with DDR1 knockdown or expressing kinase-deficient DDR1d showed 50% reduction of aligned collagen. Tractional remodeling of collagen was dependent on DDR1 clustering, activation, and interaction of the DDR1 C-terminal kinase domain with NMIIA filaments. Collagen remodeling by traction forces, DDR1 tyrosine phosphorylation, and myosin light chain phosphorylation were increased on stiff versus soft substrates. Thus, DDR1 clustering, activation, and interaction with NMIIA filaments enhance the collagen tractional remodeling that is important for collagen compaction in fibrosis.