Living cells are constantly exposed to mechanical stimuli arising from the surrounding extracellular matrix (ECM) or from neighboring cells. The intracellular molecular processes through which such physical cues are transformed into a biological response are collectively dubbed as mechanotransduction and are of fundamental importance to help the cell timely adapt to the continuous dynamic modifications of the microenvironment. Local changes in ECM composition and mechanics are driven by a feed forward interplay between the cell and the matrix itself, with the first depositing ECM proteins that in turn will impact on the surrounding cells. As such, these changes occur regularly during tissue development and are a hallmark of the pathologies of aging. Only lately, though, the importance of mechanical cues in controlling cell function (e.g., proliferation, differentiation, migration) has been acknowledged. Here we provide a critical review of the recent insights into the molecular basis of cellular mechanotransduction, by analyzing how mechanical stimuli get transformed into a given biological response through the activation of a peculiar genetic program. Specifically, by recapitulating the processes involved in the interpretation of ECM remodeling by Focal Adhesions at cell-matrix interphase, we revise the role of cytoskeleton tension as the second messenger of the mechanotransduction process and the action of mechano-responsive shuttling proteins converging on stage and cell-specific transcription factors. Finally, we give few paradigmatic examples highlighting the emerging role of malfunctions in cell mechanosensing apparatus in the onset and progression of pathologies.

/pdf/cellular-mechanotransduction-from-tension-to-function-427qws4so9.pdf

Cellular mechanotransduction: From tension to function

Lamins are intermediate filament proteins that form a scaffold, termed nuclear lamina, at the nuclear periphery. A small fraction of lamins also localize throughout the nucleoplasm. Lamins bind to a growing number of nuclear protein complexes and are implicated in both nuclear and cytoskeletal organization, mechanical stability, chromatin organization, gene regulation, genome stability, differentiation, and tissue-specific functions. The lamin-based complexes and their specific functions also provide insights into possible disease mechanisms for human laminopathies, ranging from muscular dystrophy to accelerated aging, as observed in Hutchinson–Gilford progeria and atypical Werner syndromes.

Lamins: Nuclear Intermediate Filament Proteins with Fundamental Functions in Nuclear Mechanics and Genome Regulation

Biomedical scientists use chemistry-driven processes found in nature as an inspiration to design biomaterials as promising diagnostic tools, therapeutic solutions, or tissue substitutes. While substantial consideration is devoted to the design and validation of biomaterials, the nature of their interactions with the surrounding biological microenvironment is commonly neglected. This gap of knowledge could be owing to our poor understanding of biochemical signaling pathways, lack of reliable techniques for designing biomaterials with optimal physicochemical properties, and/or poor stability of biomaterial properties after implantation. The success of host responses to biomaterials, known as biocompatibility, depends on chemical principles as the root of both cell signaling pathways in the body and how the biomaterial surface is designed. Most of the current review papers have discussed chemical engineering and biological principles of designing biomaterials as separate topics, which has resulted in neglecting the main role of chemistry in this field. In this review, we discuss biocompatibility in the context of chemistry, what it is and how to assess it, while describing contributions from both biochemical cues and biomaterials as well as the means of harmonizing them. We address both biochemical signal-transduction pathways and engineering principles of designing a biomaterial with an emphasis on its surface physicochemistry. As we aim to show the role of chemistry in the crosstalk between the surface physicochemical properties and body responses, we concisely highlight the main biochemical signal-transduction pathways involved in the biocompatibility complex. Finally, we discuss the progress and challenges associated with the current strategies used for improving the chemical and physical interactions between cells and biomaterial surface.

/pdf/biological-responses-to-physicochemical-properties-of-3i6vn14043.pdf

Biological responses to physicochemical properties of biomaterial surface.

The intermediate filament proteins, A- and B-type lamins, form the nuclear lamina scaffold adjacent to the inner nuclear membrane. B-type lamins confer elasticity, while A-type lamins lend viscosity and stiffness to nuclei. Lamins also contribute to chromatin regulation and various signaling pathways affecting gene expression. The mechanical roles of lamins and their functions in gene regulation are often viewed as independent activities, but recent findings suggest a highly cross-linked and interdependent regulation of these different functions, particularly in mechanosignaling. In this newly emerging concept, lamins act as a “mechanostat” that senses forces from outside and responds to tension by reinforcing the cytoskeleton and the extracellular matrix. A-type lamins, emerin, and the linker of the nucleoskeleton and cytoskeleton (LINC) complex directly transmit forces from the extracellular matrix into the nucleus. These mechanical forces lead to changes in the molecular structure, modification, and assembly state of A-type lamins. This in turn activates a tension-induced “inside-out signaling” through which the nucleus feeds back to the cytoskeleton and the extracellular matrix to balance outside and inside forces. These functions regulate differentiation and may be impaired in lamin-linked diseases, leading to cellular phenotypes, particularly in mechanical load-bearing tissues.

/pdf/lamins-at-the-crossroads-of-mechanosignaling-3dng32bywr.pdf

Lamins at the crossroads of mechanosignaling

Hutchinson–Gilford progeria syndrome (HGPS) is an extremely rare premature aging disease presenting many features resembling the normal aging process. HGPS patients die before the age of 20 years due to cardiovascular problems and heart failure. HGPS is linked to mutations in the LMNA gene encoding the intermediate filament protein lamin A. Lamin A is a major component of the nuclear lamina, a scaffold structure at the nuclear envelope that defines mechanochemical properties of the nucleus and is involved in chromatin organization and epigenetic regulation. Lamin A is also present in the nuclear interior where it fulfills lamina-independent functions in cell signaling and gene regulation. The most common LMNA mutation linked to HGPS leads to mis-splicing of the LMNA mRNA and produces a mutant lamin A protein called progerin that tightly associates with the inner nuclear membrane and affects the dynamic properties of lamins. Progerin expression impairs many important cellular processes providing insight into potential disease mechanisms. These include changes in mechanosignaling, altered chromatin organization and impaired genome stability, and changes in signaling pathways, leading to impaired regulation of adult stem cells, defective extracellular matrix production and premature cell senescence. In this review, we discuss these pathways and their potential contribution to the disease pathologies as well as therapeutic approaches used in preclinical and clinical tests.

/pdf/molecular-insights-into-the-premature-aging-disease-progeria-1hewb6y3op.pdf

Molecular insights into the premature aging disease progeria.

Hutchinson-Gilford progeria syndrome (HGPS) is a human progeroid disease caused by a point mutation on the LMNA gene. We reported previously that the accumulation of the nuclear envelope protein SUN1 contributes to HGPS nuclear aberrancies. However, the mechanism by which interactions between mutant lamin A (also known as progerin or LAΔ50) and SUN1 produce HGPS cellular phenotypes requires further elucidation. Using light and electron microscopy, this study demonstrated that SUN1 contributes to progerin-elicited structural changes in the nuclear envelope and the endoplasmic reticulum (ER) network. We further identified two domains through which full-length lamin A associates with SUN1, and determined that the farnesylated cysteine within the CaaX motif of lamin A has a stronger affinity for SUN1 than does the lamin A region containing amino acids 607 to 656. Farnesylation of progerin enhanced its interaction with SUN1 and reduced SUN1 mobility, thereby promoting the aberrant recruitment of progerin to the ER membrane during postmitotic assembly of the nuclear envelope, resulting in the accumulation of SUN1 over consecutive cellular divisions. These results indicate that the dysregulated interaction of SUN1 and progerin in the ER during nuclear envelope reformation determines the progression of HGPS.

Dysregulated interactions between lamin A and SUN1 induce abnormalities in the nuclear envelope and endoplasmic reticulum in progeric laminopathies

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Dysregulated interactions between lamin A and SUN1 induce abnormalities in the nuclear envelope and endoplasmic reticulum in progeric laminopathies