Compensatory CSF2-driven macrophage activation promotes adaptive resistance to CSF1R inhibition in breast-to-brain metastasis.

Tumor microenvironment-targeted therapies are emerging as promising treatment options for different cancer types. Tumor-associated macrophages and microglia (TAMs) represent an abundant nonmalignant cell type in brain metastases and have been proposed to modulate metastatic colonization and outgrowth. Here we demonstrate that targeting TAMs at distinct stages of the metastatic cascade using an inhibitor of colony-stimulating factor 1 receptor (CSF1R), BLZ945, in murine breast-to-brain metastasis models leads to antitumor responses in prevention and intervention preclinical trials.

The immune suppressive microenvironment affects efficacy of radio-immunotherapy in brain metastasis.

The tumor microenvironment in brain metastases is characterized by high myeloid cell content associated with immune suppressive and cancer-permissive functions. Moreover, brain metastases induce the recruitment of lymphocytes. Despite their presence, T-cell-directed therapies fail to elicit effective anti-tumor immune responses.

Aging-regulated anti-apoptotic long non-coding RNA Sarrah augments recovery from acute myocardial infarction.

Long non-coding RNAs (lncRNAs) contribute to cardiac (patho)physiology. Aging is the major risk factor for cardiovascular disease with cardiomyocyte apoptosis as one underlying cause. Here, we report the identification of the aging-regulated lncRNA Sarrah (ENSMUST00000140003) that is anti-apoptotic in cardiomyocytes.

Microenvironmental Regulation of Tumor Progression and Therapeutic Response in Brain Metastasis.

Cellular and non-cellular components of the tumor microenvironment (TME) are emerging as key regulators of primary tumor progression, organ-specific metastasis, and therapeutic response. In the era of TME-targeted- and immunotherapies, cancer-associated inflammation has gained increasing attention. In this regard, the brain represents a unique and highly specialized organ.

Controlling the dose-dependent, synergistic and temporal effects of NGF and GDNF by encapsulation in PLGA microparticles for use in nerve guidance conduits for the repair of large peripheral nerve defects.

Neurotrophic factor delivery via biodegradable nerve guidance conduits may serve as a promising treatment for the repair of large peripheral nerve defects. However, a platform for controlled delivery is required because of their short in vivo half-life and their potential to impede axonal regeneration when used in supraphysiological doses. In this study, we investigated the dose-dependent, synergistic and temporal effects of NGF and GDNF on neurite outgrowth, adult dorsal root ganglia axonal outgrowth, Schwann cell migration and cytokine production in vitro.

A Physicochemically Optimized and Neuroconductive Biphasic Nerve Guidance Conduit for Peripheral Nerve Repair.

Clinically available hollow nerve guidance conduits (NGCs) have had limited success in treating large peripheral nerve injuries. This study aims to develop a biphasic NGC combining a physicochemically optimized collagen outer conduit to bridge the transected nerve, and a neuroconductive hyaluronic acid-based luminal filler to support regeneration. The outer conduit is mechanically optimized by manipulating crosslinking and collagen density, allowing the engineering of a high wall permeability to mitigate the risk of neuroma formation, while also maintaining physiologically relevant stiffness and enzymatic degradation tuned to coincide with regeneration rates.

Olfactory Derived Stem Cells Delivered in a Biphasic Conduit Promote Peripheral Nerve Repair In Vivo.

Peripheral nerve injury presents significant therapeutic challenges for recovery of motor and sensory function in patients. Different clinical approaches exist but to date there has been no consensus on the most effective method of treatment. Here, we investigate a novel approach to peripheral nerve repair using olfactory derived stem (ONS) cells delivered in a biphasic collagen and laminin functionalized hyaluronic acid based nerve guidance conduit (NGC).

Roofed grooves: rapid layer engineering of perfusion channels in collagen tissue models.

Surface patterning (micro-moulding) of dense, biomimetic collagen is a simple tool to produce complex tissues using layer-by-layer assembly. The aim here was to channelise three-dimensional constructs for improved perfusion. Firstly, collagen fibril accumulation was measured by comparative image analysis to understand the mechanisms of structure formation in plastically compressed collagen during µ-moulding.

Engineering a microvascular capillary bed in a tissue-like collagen construct.

Previous studies have shown that plastic compression (PC) of collagen gels allows a rapid and controlled fabrication of matrix- and cell-rich constructs in vitro that closely mimic the structure and characteristics of tissues in vivo. Microvascular endothelial cells, the major cell type making up the blood vessels in the body, were added to the PC collagen to determine whether cells attach, survive, grow, and express endothelial cell characteristics when seeded alone or in coculture with other cells. Endothelial cells seeded on the PC collagen containing human foreskin fibroblasts (HFF) or human osteoblasts (HOS) formed vessel-like structures over 3 weeks in culture without the addition of exogenous growth factors in the medium.

Development of conical soluble phosphate glass fibers for directional tissue growth.

One of the challenges of tissue engineering is the regulation of vascularization and innervations of the implant by the host. Here, we propose that using soluble phosphate glass (SPG) fibers, incorporated in dense collagen constructs will allow us to control the rate and direction of tissue ingrowth. The idea here was to generate channels with tailored direction using conical phosphate glass fibers.

Alignment hierarchies: engineering architecture from the nanometre to the micrometre scale.

Natural tissues are built of metabolites, soluble proteins and solid extracellular matrix components (largely fibrils) together with cells. These are configured in highly organized hierarchies of structure across length scales from nanometre to millimetre, with alignments that are dominated by anisotropies in their fibrillar matrix. If we are to successfully engineer tissues, these hierarchies need to be mimicked with an understanding of the interaction between them.

Long-term neurite orientation on astrocyte monolayers aligned by microtopography.

After spinal cord injury neuronal connections are not easily re-established. Success has been hampered by the lack of orientation of neurites inside scar tissue and a lack of neurites crossing out of the site of injury. Oriented scaffolds in biodegradable polymers could be an excellent way to support both the orientation of neurites within the injury site as well as aiding their crossing out of the lesion.