microRNA Profile Changes in Brain, Cerebrospinal Fluid, and Blood Following Low-Level Repeated Blast Exposure in a Rat Model.

It is well documented that service members are exposed to repeated low-level blast overpressure during training with heavy weapons such as artillery, mortars and explosive breaching. Often, acute symptoms associated with these exposures are transient but cumulative effect of low-level repeated blast exposures (RBEs) can include persistent deficits in cognitive and behavioral health. Thus far, reliable diagnostic biomarkers which can guide countermeasure strategies have not been identified.

Differential effects on TDP-43, piezo-2, tight-junction proteins in various brain regions following repetitive low-intensity blast overpressure.

Introduction: Mild traumatic brain injury (mTBI) caused by repetitive low-intensity blast overpressure (relBOP) in military personnel exposed to breaching and heavy weapons is often unrecognized and is understudied. Exposure to relBOP poses the risk of developing abnormal behavioral and psychological changes such as altered cognitive function, anxiety, and depression, all of which can severely compromise the quality of the life of the affected individual. Due to the structural and anatomical heterogeneity of the brain, understanding the potentially varied effects of relBOP in different regions of the brain could lend insights into the risks from exposures.

JNK2 silencing lipid nanoparticles for elastic matrix repair.

The over-expression of c-Jun N-terminal kinase (JNK2), a stress activated mitogen kinase, in the aortic wall plays a critical role in the formation and progression of abdominal aortic aneurysm (AAA). This triggers chronic downstream upregulation of elastolytic matrix metalloproteinases (MMPs), MMPs2 and 9 to cause progressive proteolytic breakdown of the wall elastic matrix. We have previously shown that siNRA knockdown of JNK2 gene expression in an AAA culture model stimulates downstream elastin gene expression, elastic fiber formation, crosslinking and reduces elastolytic MMPs2 and 9.

Surface-Functionalized Stem Cell-Derived Extracellular Vesicles for Vascular Elastic Matrix Regenerative Repair.

Extracellular vesicles (EVs) are nanosized vesicles that carry cell-specific biomolecular information. Our previous studies showed that adult human bone marrow mesenchymal stem cell (BM-MSC)-derived EVs provide antiproteolytic and proregenerative effects in cultures of smooth muscle cells (SMCs) derived from an elastase-infused rat abdominal aortic aneurysm (AAA) model, and this is promising toward their use as a therapeutic platform for naturally irreversible elastic matrix aberrations in the aortic wall. Since systemically administered EVs poorly home into sites of tissue injury, disease strategies to improve their affinity toward target tissues are of great significance for EV-based treatment strategies.

Stem Cell Based Approaches to Modulate the Matrix Milieu in Vascular Disorders.

The extracellular matrix (ECM) represents a complex and dynamic framework for cells, characterized by tissue-specific biophysical, mechanical, and biochemical properties. ECM components in vascular tissues provide structural support to vascular cells and modulate their function through interaction with specific cell-surface receptors. ECM-cell interactions, together with neurotransmitters, cytokines, hormones and mechanical forces imposed by blood flow, modulate the structural organization of the vascular wall.

Adult Mesenchymal Stem Cells and Derivatives in Improved Elastin Homeostasis in a Rat Model of Abdominal Aortic Aneurysms.

Abdominal aortic aneurysms (AAAs) are localized rupture-prone expansions of the aorta with limited reversibility that develop due to proteolysis of the elastic matrix. Natural regenerative repair of an elastic matrix is difficult due to the intrinsically poor elastogenicity of adult vascular smooth muscle cells (VSMCs). This justifies the need to provide external, pro-elastin regenerative- and anti-proteolytic stimuli to VSMCs in the AAA wall towards reinstating matrix structure in the aorta wall.

Quantitative Morphometry of Elastic Fibers in Pelvic Organ Prolapse.

Pelvic organ prolapse (POP) is common among older women who have delivered children vaginally. While the pathophysiology is not fully delineated, POP can occur in part from insufficient repair of disrupted elastic matrix fibers. Quantification of structural changes to elastic fibers has not been described previously for POP.

Elastin homeostasis is altered with pelvic organ prolapse in cultures of vaginal cells from a lysyl oxidase-like 1 knockout mouse model.

Pelvic organ prolapse (POP) decreases quality of life for many women, but its pathophysiology is poorly understood. We have previously shown that Lysyl oxidase-like 1 knockout (Loxl1 KO) mice reliably prolapse with age and increased parity, similar to women. Both this model and clinical studies also indicate that altered elastin metabolism in pelvic floor tissues plays a role in POP manifestation, although it is unknown if this is a cause or effect.

Pro-elastogenic effects of mesenchymal stem cell derived smooth muscle cells in a 3D collagenous milieu.

Intrinsically poor auto-regenerative repair of proteolytically-disrupted elastic matrix structures by resident SMCs in the wall of abdominal aortic aneurysms (AAAs) prevents growth arrest and regression of these wall expansions. Supporting their possible future use in a regenerative cell therapy for AAAs, in a prior study, we showed that bone marrow mesenchymal stem cell-derived Smooth Muscle Cells (BM-SMCs) secrete biological factors that have significant pro-elastogenic and anti-proteolytic effects on aneurysmal rat aortic SMCs (EaRASMCs) in non-contact co-cultures. We also identified one stable BM-SMC phenotype (cBM-SMC) generated by differentiating BM-MSCs on a 2D fibronectin substrate in the presence of PDGF (Platelet Derived Growth Factor) and TGF-β1 (Transforming Growth Factor-β1) that exhibited superior elastogenicity and pro-elastogenic/anti-proteolytic properties.

Maintaining Elastogenicity of Mesenchymal Stem Cell-Derived Smooth Muscle Cells in Two-Dimensional Culture.

Abdominal aortic aneurysms (AAAs) are localized expansions of the abdominal aorta that grow slowly to rupture. AAA growth is driven by irreversible elastic matrix breakdown in the aorta wall by chronically upregulated matrix metalloproteases (MMPs). Since adult vascular smooth muscle cells (SMCs) poorly regenerate elastic matrix, we previously explored utility of bone marrow mesenchymal stem cells and SMCs derived therefrom (BM-SMCs) for this purpose.

Magnetically-responsive, multifunctional drug delivery nanoparticles for elastic matrix regenerative repair.

Unlabelled: Arresting or regressing growth of abdominal aortic aneurysms (AAAs), localized expansions of the abdominal aorta are contingent on inhibiting chronically overexpressed matrix metalloproteases (MMPs)-2 and -9 that disrupt elastic matrix within the aortic wall, concurrent with providing a stimulus to augmenting inherently poor auto-regeneration of these matrix structures. In a recent study we demonstrated that localized, controlled and sustained delivery of doxycycline (DOX; a tetracycline-based antibiotic) from poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs), enhances elastic matrix deposition and MMP-inhibition at a fraction of the therapeutically effective oral dose. The surface functionalization of these NPs with cationic amphiphiles, which enhances their arterial uptake, was also shown to have pro-matrix regenerative and anti-MMP effects independent of the DOX.