Recent advances of biomaterials in stem cell therapies

Stem cells have been utilized as ''living drugs'' in clinics for decades. Their self-renewal, differentiation, and immunomodulating properties provide potential solutions for a variety of malignant diseases and disorders. However, the pathological environment may diminish the therapeutic functions and survival of the transplanted stem cells, causing failure in clinical translation. To overcome these challenges, researchers have developed biomaterial-based strategies that facilitate in vivo tracking, functional engineering, and protective delivery of stem cells, paving the way for next-generation stem cell therapies. In this perspective, we briefly overview different types of stem cells and the major clinical challenges and summarize recent progress of biomaterials applied to boost stem cell therapies.

Post-Stroke Timing of ECM Hydrogel Implantation Affects Biodegradation and Tissue Restoration

Extracellular matrix (ECM) hydrogel promotes tissue regeneration in lesion cavities after stroke. However, a bioscaffold’s regenerative potential needs to be considered in the context of the evolving pathological environment caused by a stroke. To evaluate this key issue in rats, ECM hydrogel was delivered to the lesion core/cavity at 7-, 14-, 28-, and 90-days post-stroke. Due to a lack of tissue cavitation 7-days post-stroke, implantation of ECM hydrogel did not achieve a sufficient volume and distribution to warrant comparison with the other time points. Biodegradation of ECM hydrogel implanted 14- and 28-days post-stroke were efficiently (80%) degraded by 14-days post-bioscaffold implantation, whereas implantation 90-days post-stroke revealed only a 60% decrease. Macrophage invasion was robust at 14- and 28-days post-stroke but reduced in the 90-days post-stroke condition. The pro-inflammation (M1) and pro-repair (M2) phenotype ratios were equivalent at all time points, suggesting that the pathological environment determines macrophage invasion, whereas ECM hydrogel defines their polarization. Neural cells (neural progenitors, neurons, astrocytes, oligodendrocytes) were found at all time points, but a 90-days post-stroke implantation resulted in reduced densities of mature phenotypes. Brain tissue restoration is therefore dependent on an efficient delivery of a bioscaffold to a tissue cavity, with 28-days post-stroke producing the most efficient biodegradation and tissue regeneration, whereas by 90-days post-stroke, these effects are significantly reduced. Improving our understanding of how the pathological environment influences biodegradation and the tissue restoration process is hence essential to devise engineering strategies that could extend the therapeutic window for bioscaffolds to repair the damaged brain.

Emerging role of exosomes in arterial and renal calcification

Exosomes are small, cell-derived vesicles of 30–100 nm that participate in cell-to-cell communication. They are released by many cells, such as dendritic cells (DC), lymphocytes, platelets, epithelial cells, endothelial cells (EC), and are found in most body fluids, including blood, saliva, urine, and breast milk. The exosomes released from cells within the cardiovascular system may contain either inhibitors of calcification in normal physiological conditions or promoters in the pathological environment [atherosclerosis (AS), and Chronic Kidney Disease (CKD)]. The exosomes of the vascular smooth muscle cells (VSMCs) are novel players in vascular repair processes and calcification. Several studies have shown that the cytoplasmic contents of exosomes are rich in a variety of proteins, nucleic acids, and lipids. Currently, exosomal micro RNAs and proteins are increasingly being recognized as biomarkers for the diagnosis of several diseases, including those of kidney and liver, as well as different types of cancer. In this review, we summarize recent advances in the role of exosomes in vascular calcification and their potential applications as diagnostic markers as well as a brief overview of the role of stem cell-derived exosomes in cardiovascular diseases.

Microglial Plasticity Contributes to Recovery of Bone Marrow Mononuclear Cells during Experimental Stroke

Brain stroke is an acute neural disorder characterized by obstruction (ischemic) or rupture (hemorrhagic) of blood vessels causing neural damage and subsequent functional impairment. Its pathophysiology is complex and involves a multitude of pathological events including energetic collapse, excitotoxicity, oxidative stress, metabolic acidosis, cell death and neuroinflammation. Despite its clinical importance, there is no effective pharmacological therapies available to diminish secondary damage avowing functional deficits. Considering the failure of pharmacological approaches for stroke, cell therapy came as promising alternative. Different cell types have been investigated in different experimental models with promising results. An important issue regarding the transplantation of stem cells into the damaged CNS tissue is how the pathological environment influences the transplanted cells. It has been established that an exacerbated inflammation in the pathological environment is detrimental to the survival of the transplanted stem cells. This prompted us to develop an experimental strategy to improve the therapeutic actions of bone marrow mononuclear cells (BMMCs) transplanted into the acute phase of brain stroke by modulating microglial activation with minocycline. In this chapter, we first review the basic pathophysiology of ischemic stroke with emphasis on the role of microglia to the pathological outcome. We then review the experimental approach of modulating microglia activation in order to enhance therapeutic actions of BMMCS for experimental stroke. We suggest that such an approach may be applied as an adjuvant therapy to control excessive neuroinflammation in the pathological environment allowing acute transplants and improving therapeutic actions of different kind of stem cells.

Ceruloplasmin Deamidation in Neurodegeneration: From Loss to Gain of Function

Neurodegenerative disorders can induce modifications of several proteins; one of which is ceruloplasmin (Cp), a ferroxidase enzyme found modified in the cerebrospinal fluid (CSF) of neurodegenerative diseases patients. Cp modifications are caused by the oxidation induced by the pathological environment and are usually associated with activity loss. Together with oxidation, deamidation of Cp was found in the CSF from Alzheimer’s and Parkinson’s disease patients. Protein deamidation is a process characterized by asparagine residues conversion in either aspartate or isoaspartate, depending on protein sequence/structure and cellular environment. Cp deamidation occurs at two Asparagine-Glycine-Arginine (NGR)-motifs which, once deamidated to isoAspartate-Glycine-Arginine (isoDGR), bind integrins, a family of receptors mediating cell adhesion. Therefore, on the one hand, Cp modifications lead to loss of enzymatic activity, while on the other hand, these alterations confer gain of function to Cp. In fact, deamidated Cp binds to integrins and triggers intracellular signaling on choroid plexus epithelial cells, changing cell functioning. Working in concert with the oxidative environment, Cp deamidation could reach different target cells in the brain, altering their physiology and causing detrimental effects, which might contribute to the pathological mechanism.

RESENTMENT AND SOCIAL ACCEPTANCE OF LARGE FAMILIES

Facing the demographic crisis, it is worth reflecting on the issues of the place, significance and values of large family. As I. Bukalska (2017, s. 55) rightly observes, the strength of the influence of an important group of social interest, which are large families, shapes their better perception. Analyzing the content that responds to research problems on characteristics attributed to large families in source materials, media, assigned to large families and stereotyping the category of such families, it can be concluded that, despite the positive impact of these families on many aspects (e.g. demographic, economic, cultural, identity), large families still have to face unfair stereotypes of remaining a burden on society, being recipients of excessive social benefits, and even – as M. Szyszka (2015, s. 177) indicates – a pathological environment label.

Microglia Purinoceptor P2Y6: An Emerging Therapeutic Target in CNS Diseases

The purinergic receptor P2Y6 is expressed in immune cells, including the microglia that are implicated in neurological disorders. Its ligand, UDP, is a signaling molecule that can serve as an “find-me” signal when released in significant quantities by damaged/dying cells. The binding of UDP by P2Y6R leads to the activation of different biochemical pathways, depending on the disease context and the pathological environment. Generally, P2Y6R stimulates phagocytosis. However, whether or not phagocytosis coincides with cell activation or the secretion of pro-inflammatory cytokines needs further investigation. The current review aims to discuss the various functions of P2Y6R in some CNS disorders. We present evidence that P2Y6R may have a detrimental or beneficial role in the nervous system, in the context of neurological pathologies, such as ischemic stroke, Alzheimer’s disease, Parkinson’s disease, radiation-induced brain injury, and neuropathic pain.

Cu∥-loaded polydopamine coatings with in situ nitric oxide generation function for improved hemocompatibility

NO is the earliest discovered gas signal molecule which is produced by normal healthy endothelial cells, and it has many functions, such as maintaining cardiovascular homeostasis, regulating vasodilation, inhibiting intimal hyperplasia and preventing atherosclerosis in the blood system. Insufficient NO release is often observed in the pathological environment, for instance atherosclerosis. It was discovered that NO could be released from the human endogenous NO donor by many compounds, and these methods can be used for the treatment of certain diseases in the blood system. In this work, a series of copper-loaded polydopamine (PDA) coatings were produced through self-polymerization time for 24, 48 and 72 h. The chemical composition and structure, coating thickness and hydrophilicity of the different copper-loaded PDA coatings surfaces were characterized by phenol hydroxyl quantitative, X-ray photoelectron spectroscopy, ellipsometry atomic force microscopy and water contact angles. The results indicate that the thickness and the surface phenolic hydroxyl density of the PDA coatings increased with the polymerization time.This copper-loaded coating has glutathione peroxidase-like activity, and it has the capability of catalyzing NO releasing from GSNO. The surface of the coating showed desirable hemocompatibility, the adhesion and activation of platelets were inhibited on the copper-loaded coatings. At the same time, the formation of the thrombosis was also suppressed. These copper-loaded PDA coatings could provide a promising platform for the development of blood contact materials.

Role of Toll-Like Receptors in Actuating Stem/Progenitor Cell Repair Mechanisms: Different Functions in Different Cells

Toll-like receptors (TLRs) represent one of the bridges that regulate the cross-talk between the innate and adaptive immune systems. TLRs interact with molecules shared and preserved by the pathogens of origin but also with endogenous molecules (damage/danger-associated molecular patterns (DAMPs)) that derive from injured tissues. This is probably why TLRs have been found to be expressed on several kinds of stem/progenitor cells (SCs). In these cells, the role of TLRs in the regulation of the basal motility, proliferation, differentiation processes, self-renewal, and immunomodulation has been demonstrated. In this review, we analyze the many different functions that the TLRs assume in SCs, pointing out that they can have different effects, depending on the background and on the kind of ligands that they recognize. Moreover, we discuss the TLR involvement in the response of SC to specific tissue damage and in the reparative processes, as well as how the identification of molecules mediating the differential function of TLR signaling could be decisive for the development of new therapeutic strategies. Considering the available studies on TLRs in SCs, here we address the importance of TLRs in sensing an injury by stem/progenitor cells and in determining their behavior and reparative activity, which is dependent on the conditions. Therefore, it could be conceivable that SCs employed in therapy could be potentially exposed to TLR ligands, which might modulate their therapeutic potential in vivo. In this context, to modulate SC proliferation, survival, migration, and differentiation in the pathological environment, we need to better understand the mechanisms of action of TLRs on SCs and learn how to control these receptors and their downstream pathways in a precise way. In this manner, in the future, cell therapy could be improved and made safer.