Immunomechanobiology: Engineering the Activation and Function of Immune Cells with the Mechanical Signal of Fluid Shear Stress.

Immunomechanobiology, the study of how physical forces influence the behavior and function of immune cells, is a rapidly growing area of research. It is becoming increasingly recognized that mechanical stimuli, such as fluid shear forces, are a critical determinant of immune cell regulation. In this review, we discuss the principles and significance of various mechanical forces present within the human body, with a focus on fluid shear flow and its impact on immune cell activation and function.

Enhanced and sustained T cell activation in response to fluid shear stress.

The efficacy of T cell therapies in treating solid tumors is limited by poor persistence, proliferation, and cytotoxicity, which can be attributed to limited and variable activation. Herein, we present a 10-day kinetic profile of T cells subjected to fluid shear stress (FSS) , with and without stimulation utilizing bead-conjugated anti-CD3/CD28 antibodies. We demonstrate that mechanical stimulation via FSS combined with bead-bound anti-CD3/CD28 antibodies yields a synergistic effect, resulting in amplified and sustained downstream signaling (NF-κB, c-Fos, and NFAT), expression of activation markers (CD69 and CD25), proliferation and production of pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-2).

Retention of E-selectin functionalized liposome fanny packs on Jurkat cells following invasion through collagen.

Circulating immune cells are an appealing candidate to serve as carriers of therapeutic cargo via nanoparticles conjugated to their surface, for several reasons: these cells are highly migratory and can squeeze through small pores of diameter smaller than their resting size; they are easily accessible in the peripheral blood via minimally invasive IV injection of particles, or can be harvested, processed ex vivo, and reintroduced to the body; they are adept at traveling through the circulation with minimal destruction and thus have access to various tissue beds of the body; and immune cells have built-in signal transduction machinery which allows them to actively engage in chemotaxis and home to regions of the tissue containing tumors, invading microorganisms, or injuries in need of wound healing. In this study, we sought to examine and quantify the degree to which nanoscale liposomes, functionalized with E-selectin adhesion receptor, could bind to a model T cell line and remain on the surface of the cells as they migrate through collagen gels of varying density in a transwell cell migration chamber. It is demonstrated that physiological levels of fluid shear stress are necessary to achieve optimal binding of the E-selectin liposomes to the cell surface as expected, and that CD3/CD28 antibody activation of the T cells was not necessary for effective liposome binding.

Chemical Activation and Mechanical Sensitization of Piezo1 Enhance TRAIL-Mediated Apoptosis in Glioblastoma Cells.

Glioblastoma multiforme (GBM), the most common and aggressive type of primary brain tumor, has a mean survival of less than 15 months after standard treatment. Treatment with the current standard of care, temozolomide (TMZ), may be ineffective if damaged tumor cells undergo DNA repair or acquire mutations that inactivate transcription factor p53. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers apoptosis in multiple tumor types, while evading healthy cells, through a transcription-independent mechanism.

An anatomically correct 3D-printed mouse phantom for magnetic particle imaging studies.

We report anatomically correct 3D-printed mouse phantoms that can be used to plan experiments and evaluate analysis protocols for magnetic particle imaging (MPI) studies. The 3D-printed phantoms were based on the Digimouse 3D whole body mouse atlas and incorporate cavities representative of a liver, brain tumor, and orthotopic breast cancer tumor placed in anatomically correct locations, allowing evaluation of the effect of precise doses of MPI tracer. To illustrate their use, a constant tracer iron mass was present in the liver for the breast (200 μg) and brain tumor (10 μg) model, respectively, while a series of decreasing tracer iron mass was placed in the tumor region.

Channeling the Force: Piezo1 Mechanotransduction in Cancer Metastasis.

Cancer metastasis is one of the leading causes of death worldwide, motivating research into identifying new methods of preventing cancer metastasis. Recently there has been increasing interest in understanding how cancer cells transduce mechanical forces into biochemical signals, as metastasis is a process that consists of a wide range of physical forces. For instance, the circulatory system through which disseminating cancer cells must transit is an environment characterized by variable fluid shear stress due to blood flow.