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Hutchinson-Gilford progeria syndrome (HGPS) is a rare autosomal dominant genetic disease that is caused by a silent mutation of the LMNA gene encoding lamins A and C (lamin A/C). The G608G mutation generates a more accessible splicing donor site than does WT and produces an alternatively spliced product of LMNA called progerin, which is also expressed in normal aged cells. In this study, we determined that progerin binds directly to lamin A/C and induces profound nuclear aberrations. Given this observation, we performed a random screening of a chemical library and identified 3 compounds (JH1, JH4, and JH13) that efficiently block progerin-lamin A/C binding. These 3 chemicals, particularly JH4, alleviated nuclear deformation and reversed senescence markers characteristic of HGPS cells, including growth arrest and senescence-associated β-gal (SA-β-gal) activity. We then used microarray-based analysis to demonstrate that JH4 is able to rescue defects of cell-cycle progression in both HGPS and aged cells. Furthermore, administration of JH4 to LmnaG609G/G609G-mutant mice, which phenocopy human HGPS, resulted in a marked improvement of several progeria phenotypes and an extended lifespan. Together, these findings indicate that specific inhibitors with the ability to block pathological progerin-lamin A/C binding may represent a promising strategy for improving lifespan and health in both HGPS and normal aging.

Nanoscale scaffolds that characterize high bioactivity and the ability to deliver biomolecules provide a 3D microenvironment that controls and stimulates desired cellular responses and subsequent tissue reaction. Herein novel nanofibrous hybrid scaffolds of polycaprolactone shelled with mesoporous silica (PCL@MS) were developed. In this hybrid system, the silica shell provides an active biointerface, while the 3D nanoscale fibrous structure provides cell-stimulating matrix cues suitable for bone regeneration. The electrospun PCL nanofibers were coated with MS at controlled thicknesses via a sol-gel approach. The MS shell improved surface wettability and ionic reactions, involving substantial formation of bone-like mineral apatite in body-simulated medium. The MS-layered hybrid nanofibers showed a significant improvement in mechanical properties, in terms of both tensile strength and elastic modulus, as well as in nanomechanical surface behavior, which is favorable for hard tissue repair. Attachment, growth, and proliferation of rat mesenchymal stem cells were significantly improved on the hybrid scaffolds, and their osteogenic differentiation and subsequent mineralization were highly up-regulated by the hybrid scaffolds. Furthermore, the mesoporous surface of the hybrid scaffolds enabled the loading of a series of bioactive molecules, including small drugs and proteins at high levels. The release of these molecules was sustainable over a long-term period, indicating the capability of the hybrid scaffolds to deliver therapeutic molecules. Taken together, the multifunctional hybrid nanofibrous scaffolds are considered to be promising therapeutic platforms for stimulating stem cells and for the repair and regeneration of bone.

Enabling angiogenesis is critical for the success of tissue repair therapies and the fate of tissueengineered constructs. Although many biochemical signaling molecules have been used, their biological functions in vivo are known to be limited, mainly due to their short lifetime and poor activity. Matrices (or engineered biomaterials), beyond the biochemical signals, play pivotal roles in stimulating angiogenic processes. Here we discuss the proangiogenic effort taken to repair and regenerate various tissues including skin, bone, muscle and nerve, focusing on the roles of engineered matrices. This includes the design of pore structure and physico-chemical properties (nanotopology, stiffness, chemistry and degradability), the tailoring of matrices for proper presentation of growth factors and their crosstalks with adhesion ligands, the controlled and sustained delivery of angiogenic molecules and metallic ions, and the engineering of cells and construction of prevascularized tissues. Collectively, the materials-driven strategies are envisaged