Neuronal Glial Crosstalk: Specific and Shared Mechanisms in Alzheimer’s Disease

The human brain maintains billions of neurons functional across the lifespan of the individual. The glial, supportive cells of the brain are indispensable to neuron elasticity. They undergo various states (active, reactive, macrophage, primed, resting) and carefully impose either quick repair or the cleaning of injured neurons to avoid damage extension. Identifying the failure of these interactions involving the relation of the input of glial cells to the inception and/or progression of chronic neurodegenerative diseases (ND) is crucial in identifying therapeutic options, given the well-built neuro-immune module of these diseases. In the present review, we scrutinize different interactions and important factors including direct cell–cell contact, intervention by the CD200 system, various receptors present on their surfaces, CXC3RI and TREM2, and chemokines and cytokines with special reference to Alzheimer’s disease (AD). The present review of the available literature will elucidate the contribution of microglia and astrocytes to the pathophysiology of AD, thus evidencing glial cells as obligatory transducers of pathology and superlative targets for interference.

Androgen Activity in the Primary and Metastatic Prostate Cancer Microenvironments Influences Disease Progression and Patient Outcomes

Background: Cancers do not exist in isolation, surrounding tumours are supportive cells, which create the microenvironment in which cancer cells reside. In the prostate cancer (PCa), androgen receptor (AR) signalling in the surrounding fibroblasts is strikingly distinct from that within PCa cells, and has specific functions to produce, maintain, and modulate the extracellular matrix (ECM) which surrounds and interacts with PCa cells. The supportive cells of metastatic sites differ from those in the primary site and produce different types of cellular microenvironments. Since the advent of second generation anti-androgen therapy there has been an increase in the presence of liver metastasis. This project investigates how AR and anti-androgen therapy affect the prostate liver microenvironment and the subsequent effects on cancer. Results: Analysis of microenvironment of primary and metastatic sites indicates transcriptional responses distinct from that seen in PCa cells. This is exemplified by proliferation responses to androgen and anti-androgens in microenvironment cells being the reverse to that seen in Pca cells. Dichotomising microdissected PCa patient material of matched cancer and stromal tissue, based on stromal AR level shows distinct transcriptional profiles in the matched cancer cells. From previous studies, we know AR status in cancer adjacent fibroblasts (CAFs) of the primary tumor inversely associates with patient outcomes. Analysis of single cell CAFs and microdissected stromal samples points to a potential sub population of CAFs with this AR status. Conditioned media from liver and prostate fibroblast cells suggests that inactivation of AR signalling produces proliferative paracrine signals that can affect cancer cell growth. AR in primary site fibroblast and liver stellate cells regulates secretome and ECM production in the primary and metastatic site. Prostates and livers from enzalutamide treated mice showed changes in collagen fibres compared to control mice, as visualised by picro-direct-red staining. We cultured PCa cells within 3D-ECM microenvironments created in vitro from prostate fibroblasts or liver cells. The different 3D-ECM were able to produce changes in PCa cells, including gene transcription, intracellular signalling pathways, and proliferation and apoptotic responses. These data suggest that the responses of primary and metastatic microenvironments to androgens and anti-androgens can influence phosphorylation of intracellular pathways leading to alterations in gene transcription. Furthermore, the transcriptional responses of cancer cells in vitro to changes in microenvironmental AR signalling can be used to predict patient outcomes. Conclusions: Our data suggests that anti-AR therapy produces organ microenvironment-specific signals that influence the response of prostate cancer to treatments and affects patient outcomes.

A Systematic Review of the Effectiveness of Cell-Based Therapy in Repairing Peripheral Nerve Gap Defects

Nerve prostheses are widely utilized to reconstruct segmental (gap) defects in peripheral nerves as an alternative to nerve grafting. However, with increasing gap length, the effectiveness of a nerve prosthesis becomes sub-optimal, which subsequently has made repairing larger gaps in peripheral nerves a significant challenge in the field of regenerative medicine. Recently, the structure of nerve prostheses has been significantly revised, which interestingly, has provided a promising avenue for the housing and proliferation of supportive cells. In this systematic review, cell implantation in synthetic nerve prostheses to enhance the regenerative capability of an injured nerve with a focus on identifying the cell type and mode of cell delivery is discussed. Of interest are the studies employing supportive cells to bridge gaps greater than 10 mm without the aid of nerve growth factors. The results have shown that cell therapy in conjunction with nerve prostheses becomes inevitable and has dramatically boosted the ability of these prostheses to maintain sustainable nerve regeneration across larger gaps and helped to attain functional recovery, which is the ultimate goal. The statistical analysis supports the use of differentiated bone-marrow-derived mesenchymal stem cells suspended in oxygen-carrying hydrogels in chitosan prostheses for bridging gaps of up to 40 mm; however, based on the imperfect repair outcomes, nerve grafting should not yet be replaced altogether.

A magic kick for regeneration: role of mesenchymal stromal cell secretome in spermatogonial stem cell niche recovery

Background Injury of stem cell niches may disturb tissue homeostasis and regeneration coordinated by specific niche components. Yet, the mechanisms of stem cell niche restoration remain poorly understood. Herein, we examined the role of mesenchymal stromal cells (MSCs) as pivotal regulators of stem cell niche recovery focusing on the effects of their secretome. Methods The spermatogonial stem cell (SSC) niche was selected as a model. SSC niches were injured by inducing abdominal cryptorchidism in rats. Briefly, testes of anesthetized rats were elevated into the abdominal cavity through the inguinal canal for 14 days. After descent of testes, MSC or MSC secretome treatment was applied to the animals by local subtunical injections. Results Local administration of MSC or MSC secretome was sufficient to recover spermatogenesis and production of functional germ cells. The effects of MSC and their secreted components were comparable, leading to restoration of Sertoli cell pools and recovery of Leydig cell secretory functions. Conclusion Our data suggest that MSCs mimic the functions of lost supportive cells within the stem cell niche, transiently providing paracrine stimuli for target cells and triggering tissue regenerative processes after damage.