Guy M. Genin

Inherited cardiomyopathies are the leading cause of heart failure in young adults, with limited therapeutic options. Desmin-related cardiomyopathy (DRM), caused by mutations to cytoskeletal proteins and their chaperones, exemplifies this challenge: Here, protein quality control is compromised, leading to toxic protein aggregates that destroy cardiomyocyte contractile machinery. One of the deadliest DRM mutations in the chaperone protein αB crystallin (CRYAB-R120G) lacks a genetically matched preclinical model: Mouse models require massive overexpression of mutant CRYAB, raising questions about physiological relevance. Here, we establish a human model of CRYAB -linked DRM, using induced pluripotent stem cells expressing CRYAB-R120G at near-endogenous levels. We show that three-dimensional mechanical loading, but not fatty acid–based metabolic maturation media, is essential for expressing Desmin, whose aggregation defines DRM. Using microengineered heart tissues, we found that contractile deficits are associated with impaired calcium handling, pointing to electromechanical uncoupling in DRM. Treatment with the Janus kinase 1 inhibitor itacitinib partially rescued contractility, providing a functional validation of this emerging therapeutic strategy.

Axonal growth machinery is largely shared across neurons, but axons exhibit strikingly different fates depending on developmental and environmental context: sustained elongation in peripheral neurons under permissive conditions, length homeostasis in cortical neurons after target innervation, and pathological collapse into dystrophic endbulbs in injured adult central nervous system (CNS) axons. These divergent outcomes have resisted explanation by length-sensing and biomechanical models that treat long-range transport and local force generation as separate problems. We unify these phenomena through a mechanochemical model that couples bidirectional motor transport and intracellular signaling to growth-cone balance of axonal tension, actomyosin contraction, and adhesion within a single feedback loop: The lengthening axon uses its own growing transport delay to establish self-limiting mechanical feedback, as the accumulating delay reshapes signaling waveforms to progressively elevate myosin contractility against actin-driven protrusion. Two physical parameters, the transport delay and the signaling feedback strength, organize axon fate into a unified state-space landscape spanning sustained growth, length homeostasis, and pathological collapse. Reduced feedback strength weakens this self-limiting mechanical feedback by simultaneously enhancing protrusion and suppressing contractility, providing a mechanistic interpretation of axon lengthening under partial reduction of retrograde transport. Bistability in the inhibitory regime explains why mature CNS tracts persist where nascent sprouts collapse, recasting regenerative failure as a state-dependent gate rather than a capacity limit. The framework predicts that partial rather than complete inhibition of retrograde transport could shift collapsed axons across the bifurcation into a growth-permissive regime, identifying a class of interventions complementary to existing capacity-restoration strategies for nerve injury.

Nephrotic syndrome, the leading cause of chronic kidney disease worldwide, is associated with injury and eventual loss of podocytes, the specialized epithelial cells that form the final layer of the kidney’s filtration apparatus. The progression from injury to loss is largely irreversible. However, some forms of nephrotic syndrome undergo remission, suggesting that injured podocytes may retain a capacity for repair, the structural basis of which remains unknown. Podocytes respond to injury by the stereotypical morphological change known as foot process effacement (FPE), which can be visualized using transmission electron microscopy. Using modified ultrastructure expansion microscopy (U-ExM) protocol combined with super-resolution microscopy, we discovered that injured podocytes exhibit a three-stage progression of FPE maturation, with kinetics determined by the degree of actomyosin contractility. Through longitudinal study of adriamycin-induced nephropathy in mice, we identified three sequential stages of actomyosin reorganization within the sarcomere-like structures (SLSs) that define the injury response: focal infiltration of myosin IIA into synaptopodin-rich foot processes (Stage 1), disordered intermingling of synaptopodin/myosin IIA (Stage 2), and the formation of highly organized periodic contractile arrays oriented perpendicular to the direction of capillary blood flow (Stage 3). Longitudinal quantification revealed predictable temporal dynamics, with mature Stage 3 predominating by day 7-9 post-injury. To determine whether this sequence is conserved in human disease, we analyzed kidney biopsies from patients with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and diabetic nephropathy. The same three stages were present across all four diseases, and their distribution tracked disease course: acute podocytopathies exhibited heterogeneous early-stage patterns, whereas chronic injuries converged on uniform, mature SLS organization. These findings demonstrate that podocyte injury is a graded, potentially reversible process rather than a binary switch. They identify structured actomyosin remodeling as a conserved wound response across mechanistically distinct kidney diseases and suggest that therapeutic strategies targeting specific stages of this progression could alter the trajectory of diverse glomerular diseases.

Tissue‐interfaced bioelectronics require fibers that are conductive, strong, and bioactive, properties difficult to combine because conductive fillers that improve percolation tend to disrupt hydrogel networks and bioactivity. Twist densification was recently shown to convert collagen hydrogels into superhelical yarns with tendon‐like mechanics. We extend this strategy to conductive composites by incorporating silver nanowires (AgNWs) into collagen hydrogels and co‐assembling them into fibers. The completed gel network locks nanowires in place; subsequent twisting and cross‐linking induce an approximately 60‐fold volumetric densification and align collagen fibrils and AgNWs into a superhelical architecture. Incorporating the conductive phase before densification decouples electronic percolation from gel‐network formation, allowing high conductivity (>24 S/mm) and preserved collagen bioactivity to coexist in a single yarn. A quantitative model attributes this conductivity to densification‐driven volumetric percolation, alignment‐enhanced longitudinal transport, and a mechanical route to junction de‐insulation. Consistent with this model, sub‐percolating yarns show a strain‐induced decrease in resistance attributable to Poisson‐contraction‐driven junction compaction. The dense collagen matrix modulates Ag ⁺ release, suppressing the cytotoxic burst release of bare nanowires while sustaining antibacterial activity. The yarns function as conductive surgical sutures in porcine tissue and as building blocks for woven smart textiles that integrate strain sensing with electrical stimulation.

The podocyte foot process network forms the final barrier of the kidney’s glomerular filtration system. Under mechanical stress this network is prone to injury in which podocytes lose connectivity to their neighbors and begin the progression toward effacement, but what governs its mechanical resilience is unknown. We show that the network is built like a lap joint: two major processes coupled through interdigitating foot processes, a configuration that behaves as a classical shear lag system, with force concentrating at the joint ends and decaying over a characteristic transfer length set by geometry and stiffness. A discrete network model reproduces the continuum shear lag solution and identifies a hierarchy among governing parameters, with cytoskeletal stiffening of the major process amplifying foot process force more potently than basement membrane stiffness. Applying the model to morphometric data from puromycin aminonucleoside nephrosis, a model of human minimal change disease and early focal segmental glomerulosclerosis, reveals a mechanical positive feedback loop: force concentration drives foot process loss, which raises force on surviving segments and accelerates further loss. This nonlinear amplification implies a threshold beyond which failure becomes self-sustaining, analogous to the critical crack length in fracture mechanics.

Endovascular procedures require devices with widely varying mechanical properties: flexibility for navigating tortuous vessels, and rigidity for stable therapeutic delivery. Suction-actuated variable stiffness sheaths attempt to address this challenge by incorporating axial wire string arrays that couple mechanically under suction to increase flexural rigidity. However, prototype devices achieve stiffening ratios well below theoretical predictions, suggesting that string array positioning and interlayer mechanics require investigation. We therefore investigated whether interweaving expanded polytetrafluoroethylene (PTFE) tape within the string array can enhance flexural rigidity modulation and improve bending uniformity along the catheter length. Prototypes with varying PTFE wrap configurations were fabricated and evaluated using three complementary approaches. First, flexural testing revealed that flexural rigidity in the actuated and unactuated states was largely unaffected by wrapping for small deformations. Second, curvature stability testing revealed that deformation through acute simulated vascular bends was higher than expected due to two failure mechanisms: slip, in which string arrays migrate after overcoming wrap-imposed friction, and buckling, in which arrays become locally pinned and deflect against the outer lumen. Finally, a mathematical model characterized stability limits as functions of the wrapping architecture and device mechanical properties, revealing criteria for which device performance improved. Results suggest design principles for intracatheter wrapping that can narrow the gap between theoretical and achieved flexural rigidity ratios, potentially contributing to the development of endovascular devices capable of single-sheath navigation and intervention.