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Hematopoietic stem cell (HSC) regeneration is the remarkable process by which extremely rare, normally inactive cells of the bone marrow can replace an entire organ if called to do so by injury or harnessed by transplantation. HSC research is arguably the first quantitative single-cell science and the foundation of adult stem cell biology. Bone marrow transplant is the oldest and most refined technique of regenerative medicine. Here we review the intertwined history of the discovery of HSCs and bone marrow transplant, the molecular and cellular mechanisms of HSC self-renewal, and the use of HSCs and their derivatives for cell therapy.

The capacity for regeneration is broad in the animal kingdom. Planarians are flatworms that can regenerate any missing body part and their regenerative powers have combined with ease of experimentation to make them a classic regeneration model for more than a century. Pluripotent stem cells called neoblasts generate missing planarian tissues. Fate specification happens in the neoblasts, and this can occur in response to regeneration instructions in the form of positional information. Fate specification can lead to differentiating cells in single steps rather than requiring a long lineage hierarchy. Planarians display constitutive expression of positional information from muscle cells, which is required for patterned maintenance of tissues in tissue turnover. Amputation leads to the rapid resetting of positional information in a process triggered by wound signaling and the resetting of positional information is required for regeneration. These findings suggest a model for planarian regeneration in which adult positional information resets after injury to regulate stem cells to bring about the replacement of missing parts.

Here we discuss the developmental and homeostatic conditions necessary for Hydra regeneration. Hydra is characterized by populations of adult stem cells paused in the G2 phase of the cell cycle, ready to respond to injury signals. The body column can be compared to a blastema-like structure, populated with multifunctional epithelial stem cells that show low sensitivity to proapoptotic signals, and high inducibility of autophagy that promotes resistance to stress and starvation. Intact Hydra polyps also exhibit a dynamic patterning along the oral-aboral axis under the control of homeostatic organizers whose activity results from regulatory loops between activators and inhibitors. As in bilaterians, injury triggers the immediate production of reactive oxygen species (ROS) signals that promote wound healing and contribute to the reactivation of developmental programs via cell death and the de novo formation of new organizing centers from somatic tissues. In aging Hydra, regeneration is rapidly lost as homeostatic conditions are no longer pro-regenerative.

There is still limited mechanistic insight into how the interaction of individuals with their environment results in the emergence of individuality in behavior and brain structure. Nevertheless, the idea that personal activity shapes the brain is implicit in strategies for healthy cognitive aging as well as in the idea that individuality is reflected in the brain's connectome. We have shown that even isogenic mice kept in a shared enriched environment (ENR) developed divergent and stable social and exploratory trajectories. As these trajectories-measured as roaming entropy (RE)-positively correlated with adult hippocampal neurogenesis, we hypothesized that a feedback between behavioral activity and adult hippocampal neurogenesis might be a causal factor in brain individualization. We used cyclin D2 knockout mice with constitutively extremely low levels of adult hippocampal neurogenesis and their wild-type littermates. We housed them for 3 months in a novel ENR paradigm, consisting of 70 connected cages equipped with radio frequency identification antennae for longitudinal tracking. Cognitive performance was evaluated in the Morris Water Maze task (MWM). With immunohistochemistry we confirmed that adult neurogenesis correlated with RE in both genotypes and that D2 knockout mice had the expected impaired performance in the reversal phase of the MWM. But whereas the wild-type animals developed stable exploratory trajectories with increasing variance, correlating with adult neurogenesis, this individualizing phenotype was absent in D2 knockout mice. Here the behaviors started out more random and revealed less habituation and low variance. Together, these findings suggest that adult neurogenesis contributes to experience-dependent brain individualization.

Aims/hypothesis Genome-wide studies have uncovered multiple independent signals at the RREB1 locus associated with altered type 2 diabetes risk and related glycaemic traits. However, little is known about the function of the zinc finger transcription factor Ras-responsive element binding protein 1 (RREB1) in glucose homeostasis or how changes in its expression and/or function influence diabetes risk. Methods A zebrafish model lacking rreb1a and rreb1b was used to study the effect of RREB1 loss in vivo. Using transcriptomic and cellular phenotyping of a human beta cell model (EndoC-βH1) and human induced pluripotent stem cell (hiPSC)-derived beta-like cells, we investigated how loss of RREB1 expression and activity affects pancreatic endocrine cell development and function. Ex vivo measurements of human islet function were performed in donor islets from carriers of RREB1 type 2 diabetes risk alleles. Results CRISPR/Cas9-mediated loss of rreb1a and rreb1b function in zebrafish supports an in vivo role for the transcription factor in beta cell mass, beta cell insulin expression and glucose levels. Loss of RREB1 also reduced insulin gene expression and cellular insulin content in EndoC-βH1 cells and impaired insulin secretion under prolonged stimulation. Transcriptomic analysis of RREB1 knockdown and knockout EndoC-βH1 cells supports RREB1 as a novel regulator of genes involved in insulin secretion. In vitro differentiation of RREB1KO/KO hiPSCs revealed dysregulation of pro-endocrine cell genes, including RFX family members, suggesting that RREB1 also regulates genes involved in endocrine cell development. Human donor islets from carriers of type 2 diabetes risk alleles in RREB1 have altered glucose-stimulated insulin secretion ex vivo, consistent with a role for RREB1 in regulating islet cell function. Conclusions/interpretation Together, our results indicate that RREB1 regulates beta cell function by transcriptionally regulating the expression of genes involved in beta cell development and function. Graphical abstract

Introduction: Strategies of Schwann cell (SC) transplantation for regeneration of peripheral nerve injury involve many limitations. Stem cells can be used as alternative cell source for differentiation into Schwann cells. Given the high potential of neural crest-derived stem cells for the generation of multiple cell lineages, in this research, we considered whether olfactory ectomesenchymal stem cells (OE-MSCs) derived from neural crest can spontaneously differentiate into SC lineage Methods: OE-MSCs were isolated from human nasal mucosa and characterized by the mesenchymal and neural crest markers. The cells were cultured in glial growth factors-free medium and further investigated in terms of the phenotypic and functional properties. Results: Immunocytochemical staining and real-time PCR analysis indicated that the cultured OE-MSCs expressed SCs markers, SOX10, p75, S100, GFAP and MBP, differentiation indicative. It was found that the cells could secrete neurotrophic factors, including brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). Furthermore, after co-cultured with PC12, the mean neurite length was enhanced by OE-MSCs. Conclusion: The findings indicated that OE-MSCs could be differentiated spontaneously into SC-like phenotypes, suggesting their applications for transplantation in peripheral nerve injuries.

Background: Adipose mesenchymal stem cells (AMSCs) are a type of stem cell employed to repair damaged organs. This study aimed to see how effective AMSCs are at treating gentamycin- induced hepatorenal damage in rats. Methods: 18 male Wister rats were assigned into three groups; control, Gentamycin (GM), and GM+AMSCs. GM induced hepatorenal toxicity through daily injection (100 mg/kg, i.p.) for eight days. On day 9, AMSC (106 cells/ml/rat) was injected intravenously. Results : Creatinine, urea, uric acid, AST, ALP, ALT, TNF-, and MDA levels decreased, whereas IL-10, GSH, and CAT levels increased, indicating the therapeutic potency of intravenous injection AMSCs. Conclusion: The current study demonstrated the simultaneous therapeutic efficacy of adipose mesenchymal stem cells on the liver and kidney in the treatment of Gentamycin-induced hepatotoxicity. These data show that AMSCs could be a feasible therapy option for liver and kidney disease.

Significance: Nonhealing wounds are a significant burden for the health care system all over the world. Existing treatment options are not enough to promote healing, highlighting the urgent need for improved therapies. In addition, the current advancements in tissue-engineered skin constructs and stem cell-based therapies are facing significant hurdles due to the absence of a renewable source of functional cells. Recent Advances: Induced pluripotent stem cell technology (iPSC) is emerging as a novel tool to develop the next generation of personalized medicine for the treatment of chronic wounds. The iPSC provides unlimited access to various skin cells to generate complex personalized three-dimensional skin constructs for disease modeling and autologous grafts. Furthermore, the iPSC-based therapies can target distinct wound healing phases and have shown accelerating wound closure by enhancing angiogenesis, cell migration, tissue regeneration, and modulating inflammation. Critical Issues: Since the last decade, iPSC has been revolutionizing the field of wound healing and skin tissue engineering. Despite the current progress, safety and heterogeneity among iPSC lines are still major hurdles in addition to the lack of large animal studies. These challenges need to be addressed before translating an iPSC-based therapy to the clinic. Future Directions: Future considerations should be given to performing large animal studies to check the safety and efficiency of iPSC-based therapy in a wound healing setup. Furthermore, strategies should be developed to overcome variation between hiPSC lines, develop an efficient manufacturing process for iPSC-derived products, and generate complex skin constructs with vasculature and skin appendages.

Background: Human adipose-derived stem cells (hASCs) play an important role in regenerative medicine. Objective: Exploring the mechanism of Rg1 in the promotion of the proliferation and adipogenic differentiation of hASCs is important in regenerative medicine research. Methods: To observe ginsenoside Rg1 in promoting the proliferation and adipogenic differentiation of hASCs, Rg1 medium at different concentrations was established and tested using the cell counting kit-8 (CCK-8) assay, oil red O staining, alizarin red, and alcian blue. Compared to the control, differentially expressed genes (DEGs) were screened via DEG analysis, which was carried out in the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. To explore the relationship among mRNA, long non-coding RNA (lncRNA) and microRNA (miRNA), we constructed a competing endogenous RNA (ceRNA) network. Results: In this study, Rg1 was observed to promote the proliferation and adipogenic differentiation of hASCs. Additionally, enriched BPs and KEGG pathways may be involved in the promotion process, where FXR1 and Lnc-GAS5-AS1 were found to be regulatory factors. The regulatory network suggested that Rg1 could regulate the adipocytokine signaling pathway and IL−17 signaling pathway via FXR1 and Lnc-GAS5-AS1, which served as the mechanism encompassing the promotion of Rg1 on the proliferation and adipogenic differentiation of hASCs. Conclusion: A comprehensive transcriptional regulatory network related to the promotion ability of Rg1 was constructed, revealing mechanisms regarding Rg1’s promotion of the proliferation and adipogenic differentiation of hASCs. The present study provides a theoretical basis for optimizing the function of hASCs.

Gastric cancer is the fourth most common cause of cancer-linked deaths in the world. Gastric tumor cells have biological characteristics such as rapid proliferation, high invasiveness, and drug resistance, which result in recurrence and poor survival. Helicobacter pylori (H. pylori) has been proposed as a first‐class carcinogen for gastric cancer according to the 1994 world health organization (WHO) classification. One of the important mechanisms by which H. pylori affects the gastric environment and promotes carcinogenesis is triggering inflammation. H. pylori induces an inflammatory response and a plethora of different signal transduction processes, leading to gastric mucosal disturbance, chronic gastritis, and a multi-step complex pathway that initiates carcinogenesis. It seems undeniable that the interaction between various cell types, including immune cells, gastric epithelium, glands, and stem cells, is vital for the progression and development of carcinogenesis concerning H. pylori. The interactions of H. pylori with surrounding cells play a key role in cancer progression. In this review, we discuss the interplay between H. pylori and tumor-supportive cells, including mesenchymal stem cells (MSCs), cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and myeloid derived-suppressor cells (MDSCs) in gastric cancer. It is hoped that clarifying the specific mechanisms for ‘cross-talk’ between H. pylori and these cells will provide promising strategies for developing new treatments.

Accumulating evidence has demonstrated that cancer stem cells (CSCs) play an essential role in tumor progression and reoccurrence and drug resistance. Multiple signaling pathways have been revealed to be critically participated in CSC development and maintenance. Emerging evidence indicates that numerous chemopreventive compounds, also known as nutraceuticals, could eliminate CSCs in part via regulating several signaling pathways. Therefore, in this review, we will describe the some natural chemopreventive agents that target CSCs in a variety of human malignancies, including soy isoflavone, curcumin, resveratrol, tea polyphenols, sulforaphane, quercetin, indole-3-carbinol, 3,3'-diindolylmethane, withaferin A, apigenin, etc. Moreover, we discuss that eliminating CSCs by nutraceuticals might be a promising strategy for treating human cancer via overcoming drug resistance and reducing tumor reoccurrence.

Background: Cancer, a malignant tumor, is caused by the failure of the mechanism that controls cell growth and proliferation. Late clinical symptoms often manifest as lumps, pain, ulcers, and bleeding. Systemic symptoms include weight loss, fatigue, and loss of appetite. It is a major disease that threatens human life and health. How to treat cancer is a long-standing problem that needs to be overcome in the history of medicine. Discussion: In this study, we systematically review the cancer treatment evolution from traditional methods to novel approaches that include immunotherapy, nanotherapy, stem cell theapy, and gene therapy. We provide the latest review of the application status, clinical trials, and development prospects of mesenchymal stem cells and gene therapy for cancer, as well as their integration in cancer treatment. Mesenchymal stem cells are effective carriers carrying genes and provide new clinical ideas for tumor treatment. Methods: Traditional tumor treatment methods are poorly targeted, and the side effects of treatment seriously damage the physical and mental health of patients. In recent years, with the advancement of medical science and technology, the research on gene combined with mesenchymal stem cells to treat tumors has been intensified. Mesenchymal stem cells carry genes to target cancer cells, which can achieve better therapeutic effects. Conclusion: This review focuses on the current status, application prospects, and challenges of mesenchymal stem cell combined gene therapy for cancer and provides new ideas for clinical research.

In future, neurodegenerative diseases will take over cancer's place and become the major cause of death in the world, especially in developed countries. Advancements in the medical field and its facilities have led to an increase in the old age population, and thus contributing to the increase in number of people suffering from neurodegenerative diseases. Economically it is a great burden to society and the affected family. No current treatment aims to replace, protect, and regenerate lost neurons; instead, it alleviates the symptoms, extends the life span by a few months and creates severe side effects. Moreover, people who are affected are physically dependent for performing their basic activities, which makes their life miserable. There is an urgent need for therapy that could be able to overcome the deficits of conventional therapy for neurodegenerative diseases. Stem cells, the unspecialized cells with the properties of self-renewing and potency to differentiate into various cells types, can become a potent therapeutic option for neurodegenerative diseases. Stem cells have been widely used in clinical trials to evaluate their potential in curing different types of ailments. In this review, we discuss the various types of stem cells and their potential use in the treatment of neurodegenerative diseases-plural based on published preclinical and clinical studies.

Bone tissue engineering is a fast-growing field in regenerative medicine. Consequently, there is a high demand for new, fast and reliable methods to track and quantify the osteogenic differentiation of cells. Recently, a novel method was published to non-destructively quantify the hydroxyapatite content of monolayer and 3-dimensional mesenchymal stem cell cultures using the ability of 99mTechnetium-methylene diphosphonate (MDP), a well-established tracer in clinical nuclear medicine, to bind to newly synthesized hydroxyapatite. In the present study, two other commonly used 99mTechnetium tracers, 2,3-dicarboxypropane-1,1-diphosphonate (DPD) and hydroxydiphosphonate (HDP), were evaluated to see if they could also be used for the same purpose. Furthermore, we investigated if labelling at various timepoints influenced the effectiveness of the labelling. The results were analysed using one-factor ANOVA followed by Bonferroni post-hoc testing. This revealed a highly significant difference between the three osteogenic groups at each timepoint compared to their corresponding negative controls. However, there was no statistically significant difference between the three different tracers (MDP, DPD, HDP) in the osteogenic groups. Therefore all three tracers are of similar value when quantifying the extracellular hydroxylapatite content in osteogenic stem cells cultures.

Aim: This study aimed to define the expression changes and potential roles of the apoptosis-related genes in the anastasis process in breast cancer, which is one of the most common cancer types.Materials and Methods: Different types of breast cancer cell lines (MCF7 and MDA-MB-231), breast cancer stem cells, and healthy breast cell line (MCF10A) were used. Apoptotic and anastatic cell percentages were determined by the Annexin V test and flow cytometry. Gene expression changes in anastatic cells compared to apoptotic cells were determined by the qRT-PCR and 2-ΔΔCt method. The pathways and biological processes of genes that show significant changes were determined using the STRING v11.5 database.Results: In all cell groups, it was determined that the percentage of apoptosis increased as a result of ethanol application, and the percentage of apoptotic cells decreased with the removal of the apoptosis-inducing factor. The change in the percentage of apoptotic cells between the control, apoptosis, and anastasis groups was determined the most in MCF7 cells. Consistently, expression changes were determined in the largest number of genes in this cell line. CASP7 and APAF1 genes downregulated in all cell lines. In all cell groups, it was determined that anastasis affects Cysteine-type endopeptidase activity involved in execution phase of apoptosis (GO_ID: 0043027), and drug resistance-related pathways (KEGG_ID: hsa01524).Conclusion: The definition of the interaction of the anastasis phenomenon in cells with apoptosis regulatory mechanisms is important in terms of elucidating both the oncogenic transformation of healthy cells and the mechanisms of drug resistance in cancer., Amaç: Çalışmada, dünya genelinde en yaygın kanser tiplerinden biri olan meme kanserinde, apoptoz ile ilişkili genlerin anastaz sürecindeki ifadesel değişimlerinin ve potansiyel rollerinin tanımlanması amaçlanmıştır.Gereç ve Yöntem: Farklı tipteki meme kanseri hücre hatları (MCF7 ve MDA-MB-231), meme kanseri kök hücreleri ve sağlıklı meme hücre hattı (MCF10A) kullanıldı. Apoptotik ve anastatik hücre yüzdeleri, akış sitometrisi aracılığıyla Annexin V testi ile belirlendi. Apoptotik hücrelere göre anastatik hücrelerin gen ekspresyon değişimleri qRT-PCR ve 2-ΔΔCt yöntemi ile belirlendi. Anlamlı değişim gösteren genlerin görev aldıkları yolak ve biyolojik süreçler STRING v11.5 veri tabanı kullanılarak belirlendi.Bulgular: Tüm hücre gruplarında etanol uygulaması sonucu kontrole göre apoptoz yüzdesinin arttığı ve apoptozu uyaran etmenin uzaklaştırılmasıyla apoptotik hücre yüzdesinin azaldığı belirlendi. Kontrol, apoptoz ve anastaz grupları arasında apoptotik hücre yüzdesindeki değişim en fazla MCF7 hücrelerinde belirlendi. Uyumlu şekilde bu hücre hattında en fazla sayıda gende ifade değişimi belirlendi. CASP7 ve APAF1 genleri tüm hücre hatlarında ekspresyon azalışı sergiledi. Tüm hücre gruplarında anastazın sistein tipi endopeptidaz aktivitesini (GO_ID: 0043027) ve ilaç direnci ilişkili yolakları (KEGG_ID: hsa01524) ortak şekilde etkilediği belirlendi.Sonuç: Hücrelerde anastaz fenomeninin apoptoz düzenleyici mekanizmalar ile etkileşiminin tanımlanması, hem sağlıklı hücrelerin onkojenik dönüşümünün hem de kanserde ilaç direnci mekanizmalarının aydınlatılabilmesi açısından önem taşımaktadır.

Introduction SARS-CoV-2 is the pathogen of COVID-19. The virus is composed of the spike, membrane and envelope. On physiological smell, odoriferous substances bind to proteins secreted by sustentacular cells in order to be processed by olfactory receptor neurons. Olfactory disorder is one of the main manifestations of COVID-19, however, research is still required to clarify the mechanism involved in SARS-CoV-2 induced anosmia. Objective This article aims to analyze current scientific evidence intended to elucidate the pathophysiological relationship between COVID-19 and the cause of olfactory disorders. Methods Pubmed, Embase, Scopus and ScienceDirect were used to compose this article. The research was conducted on November 24th, 2020. Original articles with experimental studies in human, animal and in vitro, short communications, viewpoint, published in the English language and between 2019 and 2020 were included, all related to the pathophysiological relationship between olfactory disorders and COVID-19 infection. Results Both human cell receptors ACE2 and TMPRSS2 are essential for the SARS-CoV-2 entrance. These receptors are mostly present in the olfactory epithelium cells, therefore, the main hypothesis is that anosmia is caused due to damage to non-neuronal cells which, thereafter, affects the normal olfactory metabolism. Furthermore, magnetic resonance imaging studies exhibit a relationship between a reduction on the neuronal epithelium and the olfactory bulb atrophy. Damage to non-neuronal cells explains the average recovery lasting a few weeks. This injury can be exacerbated by an aggressive immune response, which leads to damage to neuronal cells and stem cells inducing a persistent anosmia. Conductive anosmia is not sufficient to explain most cases of COVID-19 induced anosmia. Conclusion Olfactory disorders such as anosmia and hyposmia can be caused by COVID-19, the main mechanism is associated with olfactory epithelium damage, targeting predominantly non-neuronal cells. However, neuronal cells can also be affected, worsening the condition of olfactory loss.

Recently, 3D bioprinting has been explored as a promising technology for biomedical applications with the potential to create complex structures with precise features. Cell encapsulated hydrogels composed of materials such as gelatin, collagen, hyaluronic acid, alginate and polyethylene glycol have been widely used as bioinks for 3D bioprinting. However, since most hydrogel-based bioinks may not allow rapid stabilization immediately after 3D bioprinting, achieving high resolution and fidelity to the intended architecture is a common challenge in 3D bioprinting of hydrogels. In this study, we have utilized shear-thinning and self-healing ionically crosslinked oxidized and methacrylated alginates (OMAs) as a bioink, which can be rapidly gelled by its self-healing property after bioprinting and further stabilized via secondary crosslinking. It was successfully demonstrated that stem cell-laden calcium-crosslinked OMA hydrogels can be bioprinted into complicated 3D tissue structures with both high resolution and fidelity. Additional photocrosslinking enables long-term culture of 3D bioprinted constructs for formation of functional tissue by differentiation of encapsulated human mesenchymal stem cells.

Purpose The authors describe a case of new bilateral epiretinal membranes and vitreous cells following intravitreal and subTenon's injections of bone marrow-derived stem cells. Methods Case report of a 43-year-old man with OPA-1 autosomal dominant optic atrophy who self-enrolled in a stem cell therapy clinical trial and received simultaneous bilateral intravitreal and subTenon's injections of bone marrow-derived stem cells. Results Within one month of receiving the injections, the patient developed epiretinal membranes and vitreous cells in both eyes, seen with optical coherence tomography. Conclusion Stem cell therapy has been gaining popularity as a potential intervention for progressive retinal and optic nerve diseases; however, the mechanism of action of bone marrow-derived stem cells is still not well understood and may result in unintended cell differentiation.

Central nervous system lymphoproliferative disorder (CNS-PTLD) after organ transplant is a unique clinicopathological entity and is associated with poor survival rates. When the CNS is involved, intravenous rituximab might not be the treatment of choice, due to its poor CNS penetration. However, intrathecal (IT) administration of rituximab has shown to be safe and efficient in small studies and in case series. We report here the case of a patient with late development of CNS-PTLD after kidney-pancreas transplantation who achieved complete remission after surgical resection and four cycles of IT rituximab and we provide a review of the literature for this treatment option.

With the positive outcomes of various cell therapies currently under preclinical and clinical studies, there is a significant interest in novel stem cell sources with unique therapeutic properties. Studies over the past two decades or so demonstrated the feasibility to isolate multipotent/pluripotent stem cells from hair follicles. The easy accessibility, high proliferation, and differentiation ability as well as lack of ethical concerns associated with this stem cell source make hair follicle stem cells (HFSCs) attractive candidate for cell therapy and tissue engineering. This review discusses the various stem cell types identified in rodent and human hair follicles and ongoing studies on the potential use of HFSCs for skin, bone, cardiovascular, and nerve tissue engineering. Impact statement Hair follicle stem cells are an autologous stem cell source, and recent preclinical and clinical studies demonstrated its unique properties to support and accelerate tissue regeneration, making it an attractive candidate for cell therapy and tissue engineering.

Recent developments in applied developmental physiology have provided well-defined methodologies for producing human stem cell derived cardiomyocytes. The cardiomyocytes produced have become commonplace as cardiac physiology research models. Accessibility has also allowed for the development of tissue engineered human heart constructs for drug screening, surgical intervention, and investigating cardiac pathogenesis. However, cardiac tissue engineering is an interdisciplinary field that involves complex engineering and physiological concepts, which limits its accessibility. Our review provides a readable, broad reaching, and thorough discussion of major factors to consider for the development of cardiovascular tissues from stem cell derived cardiomyocytes. In this study, our review will examine important considerations in undertaking a cardiovascular tissue engineering project and will present, interpret, and summarize some of the recent advancements in this field. Throughout, we review different forms of tissue engineered constructs, a discussion on cardiomyocyte sources, and an in-depth discussion of the fabrication and maturation procedures for tissue engineered heart constructs. Impact statement With advancements in cardiac differentiation protocols, the production of human induced pluripotent stem cell derived cardiomyocytes is becoming cost effective and routine in the laboratory setting. Monolayer based culture methods are rapidly being replaced by three-dimensional (3D) tissue engineered constructs, which are more representative of the heart geometry. In the review presented, we delve into important concepts and tissue engineering principles that should be considered when generating 3D cardiac constructs, interpreting data acquired from, and embarking on a 3D cardiac tissue-based research project.

The recent discovery of mesenchymal stem cells within periapical lesions (PL-MSC) has presented novel opportunities for managing periradicular diseases in adult teeth by way of enhancing tissue regeneration. This discovery coincides with the current paradigm shift toward biologically driven treatment strategies in endodontics, which have typically been reserved for non-vital immature permanent teeth. One such approach that shows promise is utilizing local endogenous non-collagenous dentine extracellular matrix components (dECM) to recruit and upregulate the intrinsic regenerative capacity of PL-MSCs

The need for bladder reconstruction and side effects of cystoplasty have spawned the demand for the development of alternative material substitutes. Biomaterials such as submucosa of small intestine (SIS) have been widely used as patches for bladder repair, but the outcomes are not fully satisfactory. To capture stem cells in situ has been considered as a promising strategy to speed up the process of re-cellularization and functionalization. In this study, we have developed an anti-CD29 antibody-conjugated SIS scaffold (AC-SIS) which is capable of specifically capturing urine-derived stem cells (USCs) in situ for tissue repair and regeneration. The scaffold has exhibited effective capture capacity and sound biocompatibility. In vivo experiment proved that the AC-SIS scaffold could promote rapid endothelium healing and smooth muscle regeneration. The endogenous stem cell capturing scaffolds has thereby provided a new revenue for developing effective and safer bladder patches.

Background: Phase I/II clinical trials using fetal retinal pigment epithelium (fRPE), human embryonic stem cell (hESC)-derived RPE, or human induced pluripotent stem cell (hiPSC)-derived RPE as potential sources of materials for cell-based therapy to treat degenerative retinal diseases have been carried out during the past decade. Challenges for successful translational cell-based therapy include cell manufacture, cell quality, cell storage, and cell behavior in vivo. In this study, we investigated the culture-induced changes in passaged fetal RPE, hESC-RPE and hiPSC-RPE cells in vitro and explored the differentiation and maturation effect of all-trans retinoic acid (ATRA) on those RPE cells. Methods: A total of 9 fetal RPE cell lines, hESC-RPE and hiPSC-RPE cell lines were set up using previously described methods. The culture-induced changes in subsequent passages caused by manipulating plating density, dissociation method and repeated passaging were studied by microscope, real-time quantitative PCR, western blot and immunofluorescent assays. Gene and protein expression and functional characteristics of fRPE, hESC-RPE and hiPSC-RPE incubated with ATRA at different concentration were also evaluated.Results: Compared with fRPE, hESC-RPE and hiPSC-RPE showed decreased gene and protein expression of RPE markers. Passage 3 RPE of all three types seeded at a density of 6×105 and 9x105 cells/mL in basal medium maintained pigmented polygonal, cobblestone-like morphology. RPE cells underwent mesenchymal changes showing increased expression of mesenchymal markers including a-SMA, N-cadherin, fibronectin and decreased expression of RPE markers including RPE65, E-cadherin and ZO-1, as a subsequence of low plating density, inappropriate dissociated method, and repeated passaging. fRPE, hESC-RPE and iPSC-RPE treated by ATRA at different concentrations showed increased expression of RPE markers such as RPE65, bestrophin (BEST) and CRALBP, and increased expression of negative complement regulatory proteins (CRP) including complement factor H (CFH), CD46, CD55 and CD59, and increased transepithelial resistance (TER) as well.Conclusion: Although hESC and hiPSC-derived RPE are morphologically similar to fRPE, and also have the tendency to undergo epithelial-to-mesenchymal transition (EMT) changes during the culturing and passaging process in vitro, differences in protein and gene expression among three RPE types exist. Moreover, ATRA can increase RPE markers expression, as well as to increase the expression levels of CRPs gene and protein in fRPE and stem cell-derived RPE.

Prostate cancer (PCa) is a prevalent malignancy that occurs primarily in old males. Prostate tumors in different patients manifest significant inter-patient heterogeneity with respect to histo-morphological presentations and molecular architecture. An individual patient tumor also harbors genetically distinct clones in which PCa cells display intra-tumor heterogeneity in molecular features and phenotypic marker expression. This inherent PCa cell heterogeneity, e.g., in the expression of androgen receptor (AR), constitutes a barrier to the long-term therapeutic efficacy of AR-targeting therapies. Furthermore, tumor progression as well as therapeutic treatments induce PCa cell plasticity such that AR-positive PCa cells may turn into AR-negative cells and prostate tumors may switch lineage identity from adenocarcinomas to neuroendocrine-like tumors. This induced PCa cell plasticity similarly confers resistance to AR-targeting and other therapies. In this review, I first discuss PCa from the perspective of an abnormal organ development and deregulated cellular differentiation, and discuss the luminal progenitor cells as the likely cells of origin for PCa. I then focus on intrinsic PCa cell heterogeneity in treatment-naïve tumors with the presence of prostate cancer stem cells (PCSCs). I further elaborate on PCa cell plasticity induced by genetic alterations and therapeutic interventions, and present potential strategies to therapeutically tackle PCa cell heterogeneity and plasticity. My discussions will make it clear that, to achieve enduring clinical efficacy, both intrinsic PCa cell heterogeneity and induced PCa cell plasticity need to be targeted with novel combinatorial approaches.

With the recent development of bioprinting technology, various attempts have been made to replace bioprinting technologies and regenerative medicine are more directed towards transplantation/reconstructive surgeries only with the implantation of scaffolds. The purpose of this study is to determine whether the growth factors, human umbilical cord serum (hUCS) and bFGF (basic fibroblast growth factor), have a synergistic effect on eardrum regeneration, when used with a cell-printed scaffold in a chronic tympanic membrane perforation (TMP) model. In this study, in vitro cellular activities for bioprinted cell-laden collagen scaffolds using human adipose stem cells (hASCs) and supplemented with 10 [Formula: see text]/mL hUCS and 10 ng/mL bFGF were performed. The mixture of the growth factors in the cell-laden structures effectively affects various in vitro cellular responses including the proliferation of hASCs and the migration of keratinocytes due to the synergistic effect of the growth factors and hASCs. For the in vivo evaluation, a rat TMP model was used, and the TMP regeneration was assessed by otoscopic examination, hearing threshold measurement, and histologic examination. Although the cell-laden structure containing hUCS was more enhancing effect compared to the structure with bFGF, more synergistic effect in the structure using hUCS/bFGF was observed. Based on the results, we believe that the cell-laden structure incorporating hUCS and bFGF can induce significant regeneration of chronic tympanic membrane perforation.

Early placental development lays the foundation of a healthy pregnancy, and numerous tightly regulated processes must occur for the placenta to meet the increasing nutrient and oxygen exchange requirements of the growing fetus later in gestation. Inadequacies in early placental development can result in disorders such as fetal growth restriction that do not present clinically until the second half of gestation. Indeed, growth restricted placentae exhibit impaired placental development and function, including reduced overall placental size, decreased branching of villi and the blood vessels within them, altered trophoblast function, and impaired uterine vascular remodelling, which together combine to reduce placental exchange capacity. This review explores the importance of early placental development across multiple anatomical aspects of placentation, from the stem cells and lineage hierarchies from which villous core cells and trophoblasts arise, through extravillous trophoblast invasion and spiral artery remodelling, and finally remodelling of the larger uterine vessels.

Cancer initiating/ stem cells (CSCs) undergo self-renewal and differentiation that contributes to tumor initiation, recurrence and metastasis in colorectal cancer (CRC). Targeting of colorectal cancer stem cells (CCSCs) holds significant promise in eradicating cancer cells and ultimately curing patients with cancer. In this review, we will introduce the current progress of CCSC studies, including the specific surface markers of CCSCs, the intrinsic signaling pathways that regulate the stemness and differentiation characteristics of CCSCs, and the tumor organoid model for CCSC research. We will focus on how these studies will lead to the progress in targeting specific surface markers or signaling pathways on CCSCs by monoclonal antibodies, or by natural or synthetic compounds, or by immunotherapy. As CSCs are highly heterogeneous and plastic, we suggest that combinatory approaches that target the stemness network may represent an important strategy for eradicating cancers.

BACKGROUND: Treatment with high-dose chemotherapy and stem cell transplantation has prolonged survival in patients of multiple myeloma (MM). A dose-response relationship between number of CD34+ cells infused and leukocyte and platelet recovery, exists. Patients receiving dose of 5 × 10(6)/kg (category 3), the mean (SD) neutrophil engraftment time was 11.3 (0.5) days, 10.6 (0.9) days, and 10.2 (1.3) days respectively. Platelet engraftment time was 12.4 (2.60) days, 10.6 (1.14) days, and 11.2 (1.64) days for category 1, 2, and 3 patients, respectively. Correlation co-efficient between CD 34+cell dose and days for neutrophil and platelet engraftment was found to be −0.24 and −0.20, respectively. Time for neutrophil engraftment was found to be significantly associated with CD34+ cell dose category. CONCLUSION: CD 34+ cell dose appears as the strongest predictor of leukocyte and platelet engraftment. CD 34+ cell dose of >5.0 × 10(6) cells/kg leads to an accelerated neutrophil and platelet engraftment in patients of MM.

In stem cell transplants, stem cells replace cells damaged by serve as a way for the donor's immune system to fight some types of cancer and blood-related diseases, such as leukemia, lymphoma, neuroblastoma and multiple myeloma. This research has the potential to affect the lives of Millions of people by offering unprecedented opportunities for developing new medical Therapies for debilitating diseases and a new way to explore fundamental questions of Biology. Stem cells can be guided into becoming specific cells that can be used in people to regenerate and repair tissues that have been damaged or affected by disease. People who might benefit from stem cell therapies include those with spinal cord injuries, type -1 diabetes, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, heart disease, stroke, burns, cancer and osteoarthritis. Stem cells may have the potential to be grown to become new tissue for use in transplant and regenerative medicine. Researchers continue to advance the knowledge on stem cells and their applications in transplant and regenerative medicine. Specialized types of stem cells have the ability to stop immune responses. Stem cells may therefore be very useful as a therapy for diseases in which organs are damaged or where the immune system is too active. Some types of stem cells are already used for therapy, such as the hematopoietic (blood) stem cells, which are used for the treatment of bone marrow cancer.

Platelets (small, anucleate cell fragments) derive from large precursor cells, megakaryocytes (MKs), that reside in the bone marrow. MKs emerge from hematopoietic stem cells in a complex differentiation process that involves cytoplasmic maturation, including the formation of the demarcation membrane system, and polyploidization. The main function of MKs is the generation of platelets, which predominantly occurs through the release of long, microtubule-rich proplatelets into vessel sinusoids. However, the idea of a 1-dimensional role of MKs as platelet precursors is currently being questioned because of advances in high-resolution microscopy and single-cell omics. On the one hand, recent findings suggest that proplatelet formation from bone marrow–derived MKs is not the only mechanism of platelet production, but that it may also occur through budding of the plasma membrane and in distant organs such as lung or liver. On the other hand, novel evidence suggests that MKs not only maintain physiological platelet levels but further contribute to bone marrow homeostasis through the release of extracellular vesicles or cytokines, such as transforming growth factor β1 or platelet factor 4. The notion of multitasking MKs was reinforced in recent studies by using single-cell RNA sequencing approaches on MKs derived from adult and fetal bone marrow and lungs, leading to the identification of different MK subsets that appeared to exhibit immunomodulatory or secretory roles. In the following article, novel insights into the mechanisms leading to proplatelet formation in vitro and in vivo will be reviewed and the hypothesis of MKs as immunoregulatory cells will be critically discussed.

Objective: To investigate the regenerative effects of adipose-derived mesenchymal stem cells (ADMSCs) in immortalized human keratinocyte cells (HaCaT) exposed to ultraviolet B (UVB) rays. Materials and Methods: Epidermal cells were interacted with UVB rays. Then, treatment was applied to ADMSC mediums prepared in different concentrations. Cells that did not receive UVB light were included in the study as a control. Results: With the application of human adipose tissue mesenchymal stem cells to HaCaT cells with different concentrations of media prepared, cell viability increased in both cells that received UVB radiation and those that did not. It has been observed that the said increases are more pronounced, especially in cells that have received UVB rays, reaching the maximum value at 100%, which is the highest stem cell medium concentration. ADMSC medium also had an increasing effect on the migration of UVB (+) cells. In UVB (+) cells, decreased levels of myeloid cell leukemia 1 protein (Mc1-1) and phosphorylated extracellular signal-regulated kinases (p-ERK 1/2) and dose-proportional increases were observed after treatment with stem cell medium. Conclusion: It has been determined that some factors in the ADMSC medium, especially in keratinocytes that have received UVB rays, positively support proliferation and show reparative and rejuvenating functions.

Background: Cancer is one of the leading causes of death worldwide. Chemotherapy, radiation therapy, and stem cell transplantation were the main cancer treatment approaches for several years but due to their limited effectiveness, there was a constant search for new therapeutic approaches. Cancer immunotherapy that utilizes and enhances the normal capacity of the patient's immune system was used to fight against cancer. Genetically engineered T-cells that express Chimeric Antigen Receptors (CARs) showed remarkable anti-tumor activity against hematologic malignancies and are now being investigated in a variety of solid tumors. The use of this therapy in the last few years has been successful, achieving great success in improving the quality of life and prolonging the survival time of patients with a reduction in remission rates. However, many challenges still need to be resolved in order for this technology to gain widespread adoption. Objective: This review summarizes various experimental approaches towards the use of CAR T-- cells in hematologic malignancies and solid tumors. Conclusion: Finally, we address the challenges posed by CAR T-cells and discuss strategies for improving the performance of these T-cells in fighting cancers.

As human stem cells with the special pluripotency play important roles in the innovative drug discovery and regenerative medicine, development of extracellular matrix (ECM) mimetics or functional materials that can support stem cell growth and propagation is of high significance. Despite numerous efforts spent, one major limitation restricting the wide applications of stem cells to the clinical translation is the lack of efficient strategies for low cost and large-scale stem cell production under xeno-free culture conditions. Herein, we reported a new strategy with peptides-modified polystyrene-based polymers coated onto the surface of coverslips for the growth and reproduction of human embryonic stem cells (hESCs). The modified peptides are the active parts of proteins which has been shown to contribute to the pluripotent stem cell attachment or proliferation. The peptides were linked to the glass coverslips coated by the polymer materials via chemical crosslinking, and the composite substrates successfully maintain the long-term growth of HUES-7, H7 and DF699. Our study shows that the coating of polystyrene-derived polymer modified by our developed peptides is a good matrix for long-term growth and reproduction of stem cells. This polystyrene-derived polymer substrate can be produced in large scale and stored for a long time. The most important thing is that it can support the growth of undifferentiated human pluripotent stem cells (hPSCs) for more than ten passages, which could provide a new and relatively easy way to amplify hESCs in vitro.

Cerebral conditioning is defined as the mild harmful stimuli applied to the brain before ischemia (preconditioning), during ischemia (perconditioning), immediately, a few hours or days after reperfusion (postconditioning). Various noxious stimuli can precondition, percondition or postcondition the brain, including ischemia, hypoxia or anesthetics to induce tolerance to lethal ischemia/reperfusion injury. The mechanisms underlying cerebral conditioning range from sensors and transducers including extracellular neurotransmitters and receptors, intracellular signals, transcription factors and epigenetic regulation, to effectors involving physiological protection, stem cells, heat shock proteins, Bcl-2, mitochondria, ubiquitin - proteasome pathway and autophagy pathway. Based on the large number of studies conducted in animal models, researchers explore the clinical application of cerebral conditioning. Remote ischemic conditioning is considered the most applicable and clinically relevant form of cerebral conditioning. The translational research also involves development of the biomarkers of conditioning and optimization of organ transplantation. The present review summarized the recent progress in signaling pathways and clinical applications of cerebral conditioning to explore the possibility to develop a potential therapeutic strategy for the prevention and treatment of ischemic stroke.

The aberrant biology of polyploid giant cancer cells (PGCC) includes dysregulation of the cell cycle, induction of stress responses, and dedifferentiation, all of which are likely accompanied by adaptations in biophysical properties and metabolic activity. Sphingolipids are the second largest class of membrane lipids and play important roles in many aspects of cell biology that are potentially relevant to polyploidy. We have recently shown that the function of the sphingolipid enzyme acid ceramidase (ASAH1) is critical for the ability of PGCC to generate progeny by depolyploidization but mechanisms by which sphingolipids contribute to polyploidy and generation of offspring with stem-like properties remain elusive. This review discusses the role of sphingolipids during embryonic development, cell cycle regulation, and stem cells in an effort to highlight parallels to polyploidy.

Although cross-correction was discovered more than 50 years ago, and held the promise of drastically improving disease management, still no cure exists for lysosomal storage diseases (LSDs). Cell therapies have the potential to halt disease progression: either a subset of autologous cells can be ex vivo/ in vivo transfected with the functional gene or allogenic wild type stem cells can be transplanted. However, the majority of cell-based attempts have been ineffective, due to the difficulties in reversing neuronal symptomatology, in finding appropriate gene transfection approaches, in inducing immune tolerance, reducing the risk of graft versus host disease (GVHD) when allogenic cells are used and that of immune response when engineered viruses are administered, coupled with a limited secretion and uptake of some enzymes. In the last decade, due to advances in our understanding of lysosomal biology and mechanisms of cross-correction, coupled with progresses in gene therapy, ongoing pre-clinical and clinical investigations have remarkably increased. Even gene editing approaches are currently under clinical experimentation. This review proposes to critically discuss and compare trends and advances in cell-based and gene therapy for LSDs. Systemic gene delivery and transplantation of allogenic stem cells will be initially discussed, whereas proposed brain targeting methods will be then critically outlined.

SARS-CoV-2, the virus underlying COVID-19, has now been recognized to cause multiorgan disease with a systemic effect on the host. To effectively combat SARS-CoV-2 and the subsequent development of COVID-19, it is critical to detect, monitor, and model viral pathogenesis. In this review, we discuss recent advancements in microfluidics, organ-on-a-chip, and human stem cell–derived models to study SARS-CoV-2 infection in the physiological organ microenvironment, together with their limitations. Microfluidic-based detection methods have greatly enhanced the rapidity, accessibility, and sensitivity of viral detection from patient samples. Engineered organ-on-a-chip models that recapitulate in vivo physiology have been developed for many organ systems to study viral pathology. Human stem cell–derived models have been utilized not only to model viral tropism and pathogenesis in a physiologically relevant context but also to screen for effective therapeutic compounds. The combination of all these platforms, along with future advancements, may aid to identify potential targets and develop novel strategies to counteract COVID-19 pathogenesis.

Both the canonical Wnt and androgen receptor (AR) signaling pathways are important for prostate organogenesis and homeostasis. How they crosstalk to regulate prostate stem cell behaviors remains unclear. Here, we show in lineage-tracing mouse models that although Wnt is essential for basal stem cell multipotency, ectopic Wnt activity promotes basal cell over-proliferation and squamous phenotypes, which are counteracted by elevated levels of androgen. In prostate basal cell organoids, dihydrotestosterone (DHT) antagonizes R-spondin-stimulated growth in a concentration-dependent manner. DHT down-regulates the expressions of a Wnt reporter and target genes, and RNA sequencing (RNA-seq) analyses identify Wnt signaling as a key altered pathway. Mechanistically, DHT enhances AR and β-catenin protein binding, and CUT&RUN analyses reveal that ectopic AR sequesters β-catenin away from its Wnt-related cistrome. Our results suggest that an intermediate level of Wnt activity in prostate basal stem cells, achieved via AR-β-catenin interaction, is essential for normal prostate homeostasis.

Stiffness is an important physical property of biomaterials that determines stem cell fate. Guiding stem cell differentiation via stiffness modulation has been considered in tissue engineering. However, the mechanism by which material stiffness regulates stem cell differentiation into the tendon lineage remains controversial. Increasing evidence demonstrates that immune cells interact with implanted biomaterials and regulate stem cell behaviors via paracrine signaling; however, the role of this mechanism in tendon differentiation is not clear. In this study, polydimethylsiloxane (PDMS) substrates with different stiffnesses are developed, and the tenogenic differentiation of mesenchymal stem cells (MSCs) exposed to different stiffnesses and macrophage paracrine signals is investigated. The results reveal that lower stiffnesses facilitates tenogenic differentiation of MSCs, while macrophage paracrine signals at these stiffnesses suppress the differentiation. When exposed to these two stimuli, MSCs still exhibit enhanced tendon differentiation, which is further elucidated by global proteomic analysis. Following subcutaneous implantation in rats for 2 weeks, soft biomaterial induces only low inflammation and promotes tendon-like tissue formation. In conclusion, the study demonstrates that soft, rather than stiff, material has a greater potential to guide tenogenic differentiation of stem cells, which provides comprehensive evidence for optimized bioactive scaffold design in tendon tissue engineering.

Viscoelasticity encompasses the characteristics of both the shape-conserving elasticity and the shock-absorbing viscosity. The extracellular matrices (ECM), or the protein-polymer scaffolds surrounding the cells in our body, possess unique tissue-dependent viscoelasticity to protect and provide mechanical queues to the nearby cells. Viscoelasticity in polymeric hydrogels can be achieved in several ways, one of which is by incorporating the host-guest supramolecular components. The following works explore the application of cucurbit[8]uril (CB[8])-based host-guest chemistry to achieve tuneable viscoelasticity in hydrogels. First, an ECM-mimetic CB[8]-based biomaterial tuned to the viscoelasticity of the lung is developed for stem cell engraftment into the solid organs. The crosslinker designed with a MMP-cleavable sequence enabled the enzymatic and cell-mediated changes in the gel mechanical properties, supported the organoid culture, and facilitated the functional engraftment and differentiation of the lung stem cells in the mouse lungs, highlighting the importance of tuning the viscoelasticity and cell-responsiveness of stem cell-carrying biomaterials for engraftment into solid organs. The second work reports of biofabricating the flexible electronics through a parylene surfacemodification chemistry and a novel hybrid network consisting of CB[8] and 1-benzyl-3vinylimidazolium (BVI) host-guest crosslinkers and gelatin-methacrylate (GelMA). The gel was designed to match the stress relaxation profile of the brain, facilitating a more brain ECM-mimetic biomaterial that is resistant to the high strain of the flexible neural devices. Combined with the ability to photo-pattern and combine with the different types of cells, this work presented the potential ways of multiplexing different types of biomaterials and cells to augment the bioelectronics functionalities, opening a new era of regenerative bioelectronics. The final work describes a new coumarin-based monomer that can be incorporated into the various free-radical-polymerised and-crosslinked materials to achieve reversibly phototuneable viscoelasticity. Harnessing coumarin’s UV wavelength-dependent cyclo-additionvi and-reversion, an extraordinary range ( 0.01 seconds to 1 million seconds) of stress relaxation half time (τ1/2) and storage modulus (100-10,000 Pa) were achieved with UV irradiation alone without changing the molecular composition. Unlike the previous approaches of directly functionalising the coumarin onto the polymer backbones, generating a CB[8]-coumarin monomer provided a powerful platform to augment the existing materials to possess reversibly tuneable viscoelasticity.

The characteristic maximum lifespan varies enormously across animal species from a few hours to hundreds of years. This argues that maximum lifespan, and the ageing process that itself dictates lifespan, are to a large extent genetically determined. Although controversial, this is supported by firm evidence that semelparous species display evolutionarily programmed ageing in response to reproductive and environmental cues. Parabiosis experiments reveal that ageing is orchestrated systemically through the circulation, accompanied by programmed changes in hormone levels across a lifetime. This implies that, like the circadian and circannual clocks, there is a master ‘clock of age’ (circavital clock) located in the limbic brain of mammals that modulates systemic changes in growth factor and hormone secretion over the lifespan, as well as systemic alterations in gene expression as revealed by genomic methyation analysis. Studies on accelerated ageing in mice, as well as human longevity genes, converge on evolutionarily conserved fibroblast growth factors (FGFs) and their receptors, including KLOTHO, as well as steroid hormones, as key players mediating the systemic effects of ageing. Age-related changes in these and multiple other factors are inferred to cause a progressive decline in tissue maintenance through failure of stem cell replenishment. This most severely affects the immune system, which requires constant renewal from bone marrow stem cells. Age-related immune decline increases risk of infection whereas lifespan can be extended in germfree animals. This and other evidence suggests that infection is the major cause of death in higher organisms. Immune decline is also associated with age-related diseases. Taking the example of Alzheimer’s disease (AD), we assess the evidence that AD is caused by immunosenescence and infection. The signature protein of AD brain, Aβ, is now known to be an antimicrobial peptide, and Aβ deposits in AD brain may be a response to infection rather than a cause of disease. Because some cognitively normal elderly individuals show extensive neuropathology, we argue that the location of the pathology is crucial – specifically, lesions to limbic brain are likely to accentuate immunosenescence, and could thus underlie a vicious cycle of accelerated immune decline and microbial proliferation that culminates in AD. This general model may extend to other age-related diseases, and we propose a general paradigm of organismal senescence in which declining stem cell proliferation leads to programmed immunosenescence and mortality.

A functional centrosome is vital for the development and physiology of animals. Among numerous regulatory mechanisms of the centrosome, ubiquitin-mediated proteolysis is known to be critical for the precise regulation of centriole duplication. However, its significance beyond centrosome copy number control remains unclear. Using an in vitro screen for centrosomal substrates of the APC/C ubiquitin ligase in Drosophila, we identify several conserved pericentriolar material (PCM) components, including the inner PCM protein Spd2. We show that Spd2 levels are controlled by the interphase-specific form of APC/C, APC/CFzr , in cultured cells and developing brains. Increased Spd2 levels compromise neural stem cell-specific asymmetric PCM recruitment and microtubule nucleation at interphase centrosomes, resulting in partial randomisation of the division axis and segregation patterns of the daughter centrosome in the following mitosis. We further provide evidence that APC/CFzr -dependent Spd2 degradation restricts the amount and mobility of Spd2 at the daughter centrosome, thereby facilitating the accumulation of Polo-dependent Spd2 phosphorylation for PCM recruitment. Our study underpins the critical role of cell cycle-dependent proteolytic regulation of the PCM in stem cells.

Neurons and glia of the peripheral nervous system are derived from progenitor cell populations, originating from embryonic neural crest. The neural crest and vasculature are intimately associated during embryonic development and in the mature central nervous system, in which they form a neurovascular unit comprised of neurons, glia, pericytes, and vascular endothelial cells that play important roles in health and disease. Our group and others have previously reported that postnatal populations of stem cells originating from glia or Schwann cells possess neural stem cell qualities, including rapid proliferation and differentiation into mature glia and neurons. Bone marrow receives sensory and sympathetic innervation from the peripheral nervous system and is known to contain myelinating and unmyelinating Schwann cells. Herein, we describe a population of neural crest-derived Schwann cells residing in a neurovascular niche of bone marrow in association with nerve fibers. These Schwann cells can be isolated and expanded. They demonstrate plasticity in vitro, generating neural stem cells that exhibit neurogenic potential and form neural networks within the enteric nervous system in vivo following transplantation to the intestine. These cells represent a novel source of autologous neural stem cells for the treatment of neurointestinal disorders.

The ultimate goal of regenerative medicine is to replace damaged cells, tissues or whole organs, in order to restore their proper function. Stem cell related technologies promise to generate transplants from the patients' own cells. Novel approaches such as blastocyst complementation combined with genome editing open up new perspectives for organ replacement therapies. This review summarizes recent advances in the field and highlights the challenges that still remain to be addressed.

Background: The major hurdles for successful cancer treatment are drug resistance and invasiveness developed by breast cancer stem cells (BCSC). Objective: As these two processes are highly energy-dependent, the identification of the main ATP supplier required for stem cell viability may result advantageous in the design of new therapeutic strategies to deter malignant carcinomas. Methods: The energy metabolism (glycolysis and oxidative phosphorylation, OxPhos) was systematically analyzed by assessing relevant protein contents, enzyme activities, and pathway fluxes in BCSC. Once identified as the main ATP supplier, selective energy inhibitors and canonical breast cancer drugs were used to block stem cell viability and metastatic properties. Results: OxPhos and glycolytic protein contents, as well as HK and LDH activities were several times higher in BCSC than in their parental line, MCF-7 cells. However, CS, GDH, COX activities, and both energy metabolism pathway fluxes were significantly lower (38-86%) in BCSC than in MCF-7 cells. OxPhos was the main ATP provider (>85%) in BCSC. Accordingly, oligomycin (a specific and potent canonical OxPhos inhibitor) and other non-canonical drugs with inhibitory effect on OxPhos (celecoxib, dimethylcelecoxib) significantly decreased BCSC viability, levels of epithelial-mesenchymal transition proteins, invasiveness, and induced ROS over-production, with IC50 values ranging from 1 to 20 μM in 24 h treatment. In contrast, glycolytic inhibitors (gossypol, iodoacetic acid, 3-bromopyruvate, 2-deoxyglucose) and canonical chemotherapeutic drugs (paclitaxel, doxorubicin, cisplatin) were much less effective against BCSC viability (IC50> 100 μM). Conclusion: These results indicated that the use of some NSAIDs may be a promising alternative therapeutic strategy to target BCSC.

Decellularized nerve allograft is an alternative to autologous nerve graft for nerve defects but has shown inferior clinical outcomes. Mesenchymal stem cells can play a key role in improving nerve regeneration of decellularized nerve allografts. The purpose of this study was to compare different mesenchymal stem cell seeding methods and to find the most efficient way to attach cells to nerve grafts for peripheral nerve regeneration. Wharton's jelly mesenchymal stem cells were collected from human umbilical cords and were seeded in the acellular nerve graft in five different ways as follows: PBS injection, fibrin glue drop, Matrigel drop, bioreactor, and Matrigel injection. A 6-mm sciatic nerve defect of Sprague-Dawley rats was bridged using mesenchymal stem cells-laden acellular nerve grafts according to the five seeding methods. Two days after implantation, the nerve tissue was biopsied and analyzed by the immunofluorescence staining of nuclei. The number of Wharton's jelly mesenchymal stem cells (+ h Nuclei) was counted in the inside, outside, and the total area of the graft sections under 200X magnification. The highest efficiency of mesenchymal stem cell attachment inside the graft and the highest total number of attached mesenchymal stem cells was observed in the group using Matrigel injection (p0.0001). This study showed mesenchymal stem cells can be more effectively attached to decellularized nerve graft using the injection method with Matrigel than other static or dynamic seeding methods in vivo.

Background: Cancer stem cells could influence tumor recurrence and metastasis. Objective: To develop a new effective treatment modality targeting breast cancer stem cells (BCSCs) and to explore the role of Apatinib in BCSCs. Methods: BCSCs were isolated from MDA-MB-231 cells by the immune magnetic beads method. BCSCs were treated with Apatinib, lentiviral plasmids (lncRNA ROR), and iCRT-3 (Wnt pathway inhibitors). Viability, colony numbers, sphere numbers, apoptosis, migration, invasion of BCSCs were detected by MTT, colony formation, tumorsphere, flow cytometry, wound-healing, transwell assays, respectively. The expressions of markers (ABCG2, CD44, CD90, and CD24), epithelial-mesenchymal transition (EMT)-related molecules (Ecadherin, N-cadherin, Vimentin, MMP-2, MMP-9), and Wnt/β-catenin pathway-related proteins (Wnt3a, Wnt5a, β-catenin) in breast cancer stem cells were determined by performing Western blot and qRT-PCR analysis. Results: Apatinib decreased the viability and colony numbers of BCSCs in a concentration-dependent manner, and it also reduced sphere numbers, suppressed migration, invasion and lncRNA ROR expression, and induced apoptosis of BCSCs. However, these results were partially reversed by lncRNA ROR overexpression. Apatinib suppressed stem property, EMT process, and Wnt/β-catenin pathway in BCSCs, which was partially reversed by lncRNA ROR overexpression. Moreover, lncRNA ROR overexpression increased the colony and sphere numbers and promoted the cell viability, apoptosis inhibition, migration, and invasion of BCSCs, but these effects were partially reversed by iCRT-3. LncRNA ROR overexpression increased the stem property, EMT process, and Wnt/β-catenin pathway, which were partially counteracted by iCRT-3. Conclusion: Apatinib inhibited stem property and malignant biological behaviors of BCSCs by blocking the Wnt/β-catenin signal pathway through down-regulating lncRNA ROR.