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Adult neurogenesis in the subventricular zone is a topic of intense research, since it has vast implications for the fundamental understanding of the neurobiology of the brain and its potential to being harnessed for therapy in various neurological disorders. Investigation of adult neurogenesis has been complicated by the difficulties with characterization of neural stem cells in vivo. However, recent single-cell transcriptomic studies provide more detailed information on marker expression in neural stem cells and their neuronal lineage, which hopefully will result in a more unified discussion. Regulation of the multiple biological steps in adult neurogenesis comprises intrinsic mechanisms as well as extrinsic factors which together orchestrate the process. In this review, we describe the regulating factors and their cellular sources in the physiological condition and provide an overview of the regulating factors mediating stroke-induced stimulation of neurogenesis in the subventricular zone. While there is ongoing debate about the longevity of active post-natal neurogenesis in humans, the subventricular zone has the capacity to upregulate neurogenesis in response to ischemic stroke. Though, the stroke-induced neurogenesis in humans does not seem to translate into adequate functional recovery, which opens discussion about potential treatment strategies to harness this neuroregenerative response. Various therapeutic approaches are explored in preclinical and clinical studies to target endogenous neurogenesis of which some are discussed in this review.

Dental pulp is a highly vascularized and innervated tissue containing a heterogeneous stem cell population with multilineage differentiation potential. Current endodontic treatments focus on the preservation of the pulp tissue and the regeneration of dental pulp after pathological insults. Human dental pulp stem cells (hDPSCs) are currently investigated as stem cell-based therapy for pulp regeneration and for peripheral nerve injury in which neurons and Schwann cells display limited regenerative capacity. We have developed a neuronal differentiation protocol for hDPSCs that requires neurosphere formation before neuronal maturation. Moreover, Schwann cell differentiation of hDPSCs in our group revealed that differentiated hDPSCs have acquired the ability to myelinate and guide neurites from dorsal root ganglia. Besides their dynamic differentiation capacity, hDPSCs were shown to exert a paracrine effect on neural and endothelial cells. Analysis of hDPSC conditioned medium revealed the secretion of a broad spectrum of growth factors including brain-derived neurotrophic factor, nerve growth factor, vascular endothelial growth factor, and glial-derived neurotrophic factor. Application of the conditioned medium to endothelial cells promoted cell migration and tubulogenesis, indicating a paracrine proangiogenic effect. This hypothesis was enforced by the enhanced formation of blood vessels in the chorioallantoic membrane assay in the presence of hDPSCs. In addition, transplantation of 3-dimensional-printed hydroxyapatite scaffolds containing peptide hydrogels and hDPSCs into immunocompromised mice revealed blood vessel ingrowth, pulplike tissue formation, and osteodentin deposition suggesting osteogenic/odontogenic differentiation of hDPSCs. Future studies in our research group will focus on the pulp regeneration capacity of hDPSCs and the role of fibroblasts within the pulp extracellular matrix.

Neurological disorders are characterized by neurodegeneration and/or loss of neuronal function, which cannot be adequately repaired by the host. Therefore, there is need for novel treatment options such as cell-based therapies that aim to salvage or reconstitute the lost tissue or that stimulate host repair. The present study aimed to evaluate the paracrine effects of human dental pulp stem cells (hDPSCs) on the migration and neural maturation of human SH-SY5Y neuroblastoma cells. The hDPSC secretome had a significant chemoattractive effect on SH-SY5Y cells as shown by a transwell assay. To evaluate neural maturation, SH-SY5Y cells were first induced toward neuronal cells, after which they were exposed to the hDPSC secretome. In addition, SH-SY5Y cells subjected to the hDPSC secretome showed increased neuritogenesis compared with nonexposed cells. Maturated cells were shown to increase immune reactivity for neuronal markers compared with controls. Ultrastructurally, retinoic acid (RA) signaling and subsequent exposure to the hDPSC secretome induced a gradual rise in metabolic activity and neuronal features such as multivesicular bodies and cytoskeletal elements associated with cellular communication. In addition, electrophysiological recordings of differentiating cells demonstrated a transition toward a neuronal electrophysiological profile based on the maximum tetrodotoxin (TTX)–sensitive, Na+current. Moreover, conditioned medium (CM)–hDPSC–maturated SH-SY5Y cells developed distinct features including, Cd2+-sensitive currents, which suggests that CM-hDPSC–maturated SH-SY5Y acquired voltage-gated Ca2+channels. The results reported in this study demonstrate the potential of hDPSCs to support differentiation and recruitment of cells with neuronal precursor characteristics in a paracrine manner. Moreover, this in vitro experimental design showed that the widely used SH-SY5Y cell line can improve and simplify the preclinical in vitro research on the molecular mechanisms of stem cell–mediated neuronal regeneration.

Pathologies of the central nervous system are characterized by loss of brain tissue and neuronal function which cannot be adequately restored by endogenous repair processes. This stresses the need for novel treatment options such as cell-based therapies that are able to restore damaged tissue or stimulate repair. This study investigated the neuroregenerative potential of the conditioned medium of human dental pulp stem cells (CM-hDPSCs) on neural stem cell (NSC) proliferation and migration as well as on neurite outgrowth of primary cortical neurons (pCNs). Additionally, the effect of leukocyte- and platelet-rich fibrin (L-PRF) priming on the neuroregenerative potential of the hDPSC secretome on NSCs and pCNs was evaluated. L-PRF contains factors that enhance stem cell-induced regeneration, but its effect on hDPSC-mediated neuroregeneration is unknown. This study demonstrated that CM-hDPSCs enhanced neuritogenesis. Moreover, CM-hDPSCs had a chemoattractant effect on NSCs. Although priming hDPSCs with L-PRF increased brain-derived neurotrophic factor secretion, no additional effects on the paracrine-mediated repair mechanisms were observed. These data support the neuroregenerative potential of hDPSCs, and although priming had no additional effect, the potential of L-PRF-primed hDPSCs on distinct regenerative mechanisms remains to be clarified. The authors would like to send out a word of gratitude to Mr. Marc Jans for his expertise in preparing TEM samples and to Dr. Dearbhaile Dooley for her help with the isolation of NSCs. Pascal Gervois, Esther Wolfs, Jessica Ratajczak, Tim Vangansewinkel, Yörg Dillen, Annelies Bronckaers, and Ivo Lambrichts are funded by FWO grants 12U7718N, G0A7514N, G089213N, G029112N, 1134717N, 1508015N, and G026112N. Greet Merckx is supported by Bijzonder Onderzoeksfonds grant BOF16DOC06.

Stroke is the second most common cause of death and is a major cause of permanent disability. Given the current demographic trend of an ageing population and associated increased risk, the prevalence of and socioeconomic burden caused by stroke will continue to rise. Current therapies are unable to sufficiently ameliorate the disease outcome and are not applicable to all patients. Therefore, strategies such as cell-based therapies with mesenchymal stem cell (MSC) or induced pluripotent stem cell (iPSC) pave the way for new treatment options for stroke. These cells showed great preclinical promise despite the fact that the precise mechanism of action and the optimal administration route are unknown. To gain dynamic insights into the underlying repair processes after stem cell engraftment, noninvasive imaging modalities were developed to provide detailed spatial and functional information on the donor cell fate and host microenvironment. This review will focus on MSCs and iPSCs as types of widely used stem cell sources in current (bio)medical research and compare their efficacy and potential to ameliorate the disease outcome in animal stroke models. In addition, novel noninvasive imaging strategies allowing temporospatial in vivo tracking of transplanted cells and coinciding evaluation of neuronal repair following stroke will be discussed.

Bacterial genomes accommodate a variety of mobile genetic elements, including bacteriophage-related clusters that encode phage tail-likeprotein complexesplaying a role ininteractions with eukaryoticorprokaryotic cells. Such tailocins areunable toreplicate inside target cells due to the lack of a phage head with associatedDNA. Asubset of tailocins mediate antagonistic activitieswith bacteriocin-like specificity. Functional characterization of bactericidal tailocins of two Pseudomonas putida rhizosphere isolates revealed not only extensive similarity with the tail assembly module of the Pseudomonas aeruginosa R-type pyocins but also differences in genomic integration site, regulatory genes, and lytic releasemodules. Conversely, these three features are quite similar between strains of the P. putidaandPseudomonasfluorescens clades, althoughphylogenetic analysisof tailgenes suggeststhemtohave evolved separately. Unlike P. aeruginosa R pyocin elements, the tailocin gene clusters of other pseudomonads frequently carry cargo genes, including bacteriocins. Compared with P. aeruginosa, the tailocin tail fiber sequences that act as specificity determinants have divergedmuch more extensively among the other pseudomonad species, mostly isolates from soil and plant environments. Activity of the P. putida antibacterial particles requires a functional lipopolysaccharide layer on target cells, but contrary to R pyocins from P. aeruginosa, strain susceptibilities surpass species boundaries. This work was partially supported by the FNRS under grant "Grand equipement" no. 2877824 to R.W. M.G.K.G. is the recipient of an FWO postdoctoral fellowship (12M4615N). The authors thank Dr Sandra Van Puyvelde for technical assistance. They acknowledge the valuable comments provided by the reviewers.

Worldwide, stroke is the second single most common cause of death and is a major cause of permanent disability. Moreover, the highest incidence of these pathologies is observed in the elderly, increasing the socioeconomic burden in an aging population. Current available therapies lead to insufficient functional improvement or are not applicable to all patients. This stresses the urgent need for alternative strategies in treating stroke patients, for example cell-based therapies. These cells showed great preclinical potential although the underlying therapeutic mechanisms, preferential route of administration and most suitable stem cell-subtype are unknown. Mechanisms of action include neuroprotection, cell replacement, neurogenesis, immunomodulation and the promotion of both neuroplasticity and angiogenesis in damaged central nervous system regions. Moreover, stem cells have been genetically engineered to enhance their beneficial effects after transplantation. Additionally, noninvasive imaging can be used to provide detailed spatial and functional information on the donor cell fate and the response of the host microenvironment. This chapter provides an overview of recent advances in (bio-)medical research using or manipulating stem cell-based therapies for ischaemic stroke with a focus on their neuroprotective, neuroregenerative and immunomodulatory properties. Additionally, the use of noninvasive imaging to allow temporospatial evaluation of stem cell fate following transplantation in animal stroke models will be discussed.

Over the past decade, dental tissues have become an attractive source of mesenchymal stem cells (MSCs). Dental stem cells (DSCs) are not only able to differentiate into adipogenic, chondrogenic and osteogenic lineanges, but an increasing amount of research also pointed out their potential applicability in numerous clinical disorders, such as myocardial infarction, neurodegenerative diseases and diabetes. Together with their multilineage differentiation capacity, their easy availability from extracted third molars makes these stem cells a suitable alternative for bone marrow-derived MSCs. More importantly, DSCs appear to retain their stem cell properties following cryopreservation, a key aspect in their long-term preservation and upscale production. However, the vast number of different cryopreservation protocols makes it difficult to draw definite conclusions regarding the behavior of these stem cells. The routine application and banking of DSCs is also associated with some other pitfalls, such as interdonor variability, cell culture-induced changes and the use of animal-derived culture medium additives. Only thorough assessment of these challenges and the implementation of standardized, GMP procedures will successfully lead to better treatment options for patients who no longer benefit from current stem cell therapies.

Stroke is the second most common cause of death and is a major cause of permanent disability. Given the current demographic trend of an ageing population and associated increased risk, the prevalence of and socioeconomic burden caused by stroke will continue to rise. Current therapies are unable to sufficiently ameliorate the disease outcome and are not applicable to all patients. Therefore, strategies such as cell-based therapies with mesenchymal stem cell (MSC) or induced pluripotent stem cell (iPSC) pave the way for new treatment options for stroke. These cells showed great preclinical promise despite the fact that the precise mechanism of action and the optimal administration route are unknown. To gain dynamic insights into the underlying repair processes after stem cell engraftment, noninvasive imaging modalities were developed to provide detailed spatial and functional information on the donor cell fate and host microenvironment. This review will focus on MSCs and iPSCs as types of widely used stem cell sources in current (bio)medical research and compare their efficacy and potential to ameliorate the disease outcome in animal stroke models. In addition, novel noninvasive imaging strategies allowing temporospatial in vivo tracking of transplanted cells and coinciding evaluation of neuronal repair following stroke will be discussed.

Within the field of tissue engineering, natural tissues are reconstructed by combining growth factors, stem cells, and different biomaterials to serve as a scaffold for novel tissue growth. As adequate vascularization and innervation are essential components for the viability of regenerated tissues, there is a high need for easily accessible stem cells that are capable of supporting these functions. Within the human tooth and its surrounding tissues, different stem cell populations can be distinguished, such as dental pulp stem cells, stem cells from human deciduous teeth, stem cells from the apical papilla, dental follicle stem cells, and periodontal ligament stem cells. Given their straightforward and relatively easy isolation from extracted third molars, dental stem cells (DSCs) have become an attractive source of mesenchymal-like stem cells. Over the past decade, there have been numerous studies supporting the angiogenic, neuroprotective, and neurotrophic effects of the DSC secretome. Together with their ability to differentiate into endothelial cells and neural cell types, this makes DSCs suitable candidates for dental tissue engineering and nerve injury repair.

Throughout time humans have been born with the curiosity to explore. Crossing the oceans on Earth to those in interplanetary space, the motivations behind exploration by humanity have not changed profoundly during these last five centuries. Some of the obstacles that were met by the explorers in the past and those that we will encounter in the future are similar, funding issues being one such topic. However, obstacles regarding the environmental conditions that will be encountered in interplanetary space are very different from those found on Earth. Indeed, the space weather that presides in interplanetary space is unlike anything we are familiar with in our daily lives. However, be it an ocean storm or a solar storm, the objective remains the same-to understand and protect the transportation device and the crew against the environment that it will encounter.