Surgical site infection increases the risk of morbidity and mortality in patients; among them, aortic graft infections present a poor prognosis. Previous clinical studies have demonstrated the efficacy of omentum flaps, a type of adipose tissue containing mesenchymal stem cells, in inhibiting SSI development in cardiothoracic surgery. However, how omental tissues prevent bacterial infection is still under investigation. Although mesenchymal stem cell is a type of cells that are reported to possess the ability to control infection, most studies have used mesenchymal stem cells derived from bone marrow or subcutaneous adipose tissues and the antibacterial properties of those derived from omentum (oAT-MSC) are still obscured. In the present study, we found that conditioned media (CM) derived from oAT-MSC possessed the ability to impair the growth of S. aureus and MRSA strains, similar to those derived from mesenchymal stem cells of subcutaneous adipose tissue. In addition, concentrated CM from oAT-MSC protected endothelial cells, preserving their morphology and functionality and reducing intracellular ROS following bacterial exposure. Furthermore, in a mouse infection model with S. aureus, concentrated CM from oAT-MSC supported mouse survival and facilitated post-infection wound healing by promoting re-epithelialization and vascularization. A transcriptomic profile analysis of oAT-MSC revealed the high expression of serpine1, encoding for PAI-1 as a secreted agent involved in protecting endothelial functions under S. aureus infection. Our findings suggest a role for oAT-MSC in the efficacy of omentum grafts in cardiothoracic surgery to prevent S. aureus. Additionally, with the ability to prevent infections and preserve the endothelial function under pathological conditions, oAT-MSC-derived secretome could potentially be an effective cell-free tool for S. aureus infection control and improvement of clinical outcomes in surgeries.

Primary Müller glia (MG) have been reported to exhibit a neurogenic capacity induced by small molecules. However, whether immortalized mouse MG cell lines exhibit neurogenic capacities similar to those of primary mouse MG remains unclear. In this study, we examined the morphology, proliferation rate, and marker profile of primary MG cells isolated from postnatal mouse pups with two immortalized mouse MG cell lines, QMMuC-1 and ImM10, in a standard growth medium. After chemical induction, we compared the morphology, markers, direct neuronal reprogramming efficiency, and axon length of these cell types in two culture media: Neurobasal and DMEM/F12. Our results showed that in standard growth medium, QMMuC-1 and ImM10 cells displayed similar morphology and marker profiles as primary MG cells, with the only differences observed in nestin expression. However, QMMuC-1 and ImM10 cells exhibited much higher proliferation rates than the primary MG cells. Following chemical treatment in both Neurobasal and DMEM/F12 media, a subset of primary MG, QMMuC-1, and ImM10 cells was induced to differentiate into immature neuron-like cells by day 7. While primary MG cells showed similar neuronal reprogramming efficiency and axon length extension in both media, QMMuC-1 and ImM10 cells displayed variations between the two culture media. Moreover, some of the induced neuronal cells derived from primary MG cells expressed HuC/D and Calbindin markers, whereas none of the cells derived from QMMuC-1 and ImM10 cells expressed these markers. Subsequent observations revealed that induced immature neuron-like cells derived from primary MG cells in both types of media and those derived from ImM10 cells cultured in DMEM/F12 survived until day 14. Taken together, our findings suggest that the two immortalized cell lines, QMMuC-1 and ImM10, exhibited neurogenic capacities similar to those of primary MG cells to some extent but did not fully recapitulate all their characteristics. Therefore, careful consideration should be given to culture conditions and the validation of key results when using immortalized cells as a substitute for primary MG cells.

IntroductionSARS-CoV-2 infection increases the risk of worse outcomes in cancer patients, including those with breast cancer. Our previous study reported that the SARS-CoV-2 membrane protein (M-protein) promotes the malignant transformation of triple-negative breast cancer cells (triple-negative BCC).MethodsIn the present study, the effects of M-protein on the ability of extracellular vesicles (EV) derived from triple-negative BCC to regulate the functions of tissue stem cells facilitating the tumor microenvironment were examined.ResultsOur results showed that EV derived from M-protein-induced triple-negative BCC (MpEV) significantly induced the paracrine effects of adipose tissue-derived mesenchymal stem cells (ATMSC) on non-aggressive BCC, promoting the migration, stemness phenotypes, and in vivo metastasis of BCC, which is related to PGE2/IL1 signaling pathways, in comparison to EV derived from normal triple-negative BCC (nEV). In addition to ATMSC, the effects of MpEV on endothelial progenitor cells (EPC), another type of tissue stem cells, were examined. Our data suggested that EPC uptaking MpEV acquired a tumor endothelial cell-like phenotype, with increasing angiogenesis and the ability to support the aggressiveness and metastasis of non-aggressive BCC.DiscussionTaken together, our findings suggest the role of SARS-CoV-2 M-protein in altering the cellular communication between cancer cells and other non-cancer cells inside the tumor microenvironment via EV. Specifically, M-proteins induced the ability of EV derived from triple-negative BCC to promote the functions of non-cancer cells, such as tissue stem cells, in tumorigenesis.

The risk of severe disease caused by co-infection with SARS-CoV-2 and influenza virus (IAV) raises an annual concern for global public health. Extracellular vesicles (EV) derived from mesenchymal stem cells (MSC) possess anti-inflammatory properties that can attenuate the inflammatory cytokine levels induced by viral infection. However, the effects of MSC-EV treatment on SARS-CoV-2 and IAV co-infection have not been elucidated. In the present study, we co-induced lung epithelial cells (EpiC) with SARS-CoV-2 Spike protein (S) and H1N1 influenza viral HA protein (HA) and found robust upregulation of inflammatory cytokines in comparison to those induced by either S or HA protein. Consequently, treatment of lung endothelial cells (EC) with conditioned medium from EpiC co-induced by both S and HA proteins resulted in increased apoptosis and impaired angiogenic ability, suggesting the effects of co-induction on epithelial-endothelial crosstalk. In addition, lung EpiC co-induced by both S and HA proteins showed paracrine effects on the recruitment of immune cells, including monocytes, macrophages and neutrophils. Of Note, EV derived from Wharton Jelly’s MSC (WJ-EV) transferred miR-146a to recipient lung EpiC, which impaired TRAF6 and IRAK1, resulting in the downregulation of NF-κB pathway and secretion of inflammatory cytokines, rescuing the epithelial-endothelial crosstalk, and reducing the elevation of immune cell recruitment. Moreover, the anti-inflammatory properties of WJ-EV are affected by type 2 Diabetes Mellitus. WJ-EV derived from donors with type 2 Diabetes Mellitus contained less miR-146a and showed impaired ability to downregulate the NF-κB pathway and inflammatory cytokines in recipient cells. Taken together, our findings demonstrate the role of miR-146a in targeting the NF-κB pathway in the anti-inflammatory abilities of WJ-EV, which is a promising strategy to rescue the epithelial-endothelial crosstalk altered by co-infection with SARS-CoV-2 and IAV.

Type 2 diabetes mellitus (T2DM) is associated with endothelial dysfunction, which results in delayed wound healing. Mesenchymal stem cells (MSCs) play a vital role in supporting endothelial cells (ECs) and promoting wound healing by paracrine effects through their secretome-containing extracellular vesicles. We previously reported the impaired wound healing ability of adipose tissue-derived MSC from T2DM donors; however, whether extracellular vesicles isolated from T2DM adipose tissue-derived MSCs (dEVs) exhibit altered functions in comparison to those derived from healthy donors (nEVs) is still unclear. In this study, we found that nEVs induced EC survival and angiogenesis, whereas dEVs lost these abilities. In addition, under high glucose conditions, nEV protected ECs from endothelial-mesenchymal transition (EndMT), whereas dEV significantly induced EndMT by activating the transforming growth factor-β/Smad3 signaling pathway, which impaired the tube formation and in vivo wound healing abilities of ECs. Interestingly, the treatment of dEV-internalized ECs with nEVs rescued the induced EndMT effects. Of note, the internalization of nEV into T2DM adipose tissue-derived MSC resulted in the production of an altered n-dEV, which inhibited EndMT and supported the survival of T2DM db/db mice from severe wounds. Taken together, our findings suggest the role of dEV in endothelial dysfunction and delayed wound healing in T2DM by the promotion of EndMT. Moreover, nEV treatment can be considered a promising candidate for cell-free therapy to protect ECs in T2DM.

IntroductionThe growing problem of antimicrobial resistance (AMR) poses a significant challenge to public health; This is partly due to the lack of advancements in the development of novel antibiotics and the pressing need for alternative treatment options. Mesenchymal stem cells (MSC) possess secretory components that enhance the immune response and peptides that disrupt the bacteria constitution. The isolation of various human tissues has facilitated the investigation of the diverse potentials of MSC and their components. Further research is needed to fully understand the spectrum and efficacy of these elements and their differences. The primary aim of this study was to perform a thorough review of the current literature related to the antimicrobial properties of MSC and their associated components. The objective was to establish an insight into the results and effects of utilizing MSC in relation to bacterial colonization, and to present an overview of previously documented findings.MethodsThis systematic literature review was conducted using the PubMed, Embase, and Web of Science databases. Data on the effect of MSC or their derivatives were measured by calculating the percentage of bacterial counts reduction after treatment with MSC in comparison to the control.ResultsA total of 3,911 articles were screened, and 31 eligible publications were selected for inclusion in the analysis. In the current systematic review, the majority of the experimental designs showed positive outcomes in terms of bacterial load reduction when MSC or their derivatives were used, with bone marrow being the most effective tissue. The rest of the findings exhibited heterogeneity in the spectrum of outcomes that could be attributed to the effects of using various tissues derived MSC in both in vivo and in vitro studies.ConclusionThe findings of our study indicate the potential antibacterial characteristics of MSC. The direct antimicrobial activity of these cells was demonstrated by our results, which quantitatively showed a decrease in bacterial growth after treatment with MSC. However, additional research is required to clarify the factors that determine the efficacy of their antimicrobial activity and their various components.

Background: The spread of the COVID-19 pandemic significantly influences cancer patients, not only in terms of cancer care but also cancer progression after SARS-CoV-2 viral infection. Although patients could recover from COVID-19, post-COVID-19 syndrome remains a concern. However, there is little work on the impact of SARS-CoV-2 infection on cancer cells and its mechanism. Therefore, our study aims to investigate the impacts of SARS-CoV-2 proteins on breast cancer cells (BCCs) and their consequences on the tumor microenvironment.

Glucocorticoids are common anti-inflammatory factors; however, they have been reported to have side effects that delay the wound healing process. In a previous study, we found that mesenchymal stem cells isolated from the adipose tissue of patients with long-term glucocorticoid treatment (sAT-MSC) showed impaired wound healing ability due to the downregulation of SDF-1. In this study, we aimed to clarify the mechanisms by which SDF-1 is regulated in sAT-MSC by focusing on the roles of hypoxia-inducible factors (HIFs). Our data suggested that sAT-MSC showed impairment of HIF-1α and the upregulation of HIF-2α. Notably, HIF-2α impairment resulted in the compensatory overexpression of HIF-1α and its target gene SDF-1, which improved the wound healing ability of sAT-MSC. In addition, using knockdown/knockout heterozygous HIF-2α kd/null mice (kd/null), the functions of HIF-2α in the ischemic wound healing process were clarified. With a 50% reduction in the expression of HIF-2α, kd/null mice showed significantly induced wound healing effects, which are involved in the promotion of the inflammatory phase. Specifically, kd/null mice showed the compensatory overexpression of HIF-1α, which upregulated the expression of SDF-1 and enhanced the recruitment of inflammatory cells, such as neutrophils. Our study highlighted the novel function of HIF-2α in the inflammation phase of the wound healing process through the HIF-1α/SDF-1 axis, suggesting that the physiological state of the impaired expression of HIF-2α is a new concept for wound therapy.

Triple-negative breast cancer (TNBC) is a highly aggressive and invasive type of breast cancer. In addition, type 2 diabetes mellitus (T2DM) is recognized as a risk factor for cancer metastasis, which is associated with mortality in patients with breast cancer. Cancer-associated fibroblasts (CAFs) generated from adipose tissue-derived mesenchymal stem cells (AT-MSCs) play a vital role in the progression of TNBC. However, to date, whether T2DM affects the ability of AT-MSCs to differentiate into CAFs is still unclear. In this study, we found that in coculture with TNBC cells [breast cancer cells (BCCs)] under hypoxic conditions, AT-MSCs derived from T2DM donors (dAT-MSCs) were facilitated to differentiate into CAFs, which showed fibroblastic morphology and the induced expression of fibroblastic markers, such as fibroblast activation protein, fibroblast-specific protein, and vimentin. This was involved in the higher expression of transforming growth factor beta receptor 2 (TGFβR2) and the phosphorylation of Smad2/3. Furthermore, T2DM affected the fate and functions of CAFs derived from dAT-MSCs. While CAFs derived from AT-MSCs of healthy donors (AT-CAFs) exhibited the markers of inflammatory CAFs, those derived from dAT-MSCs (dAT-CAFs) showed the markers of myofibroblastic CAFs. Of note, in comparison with AT-CAFs, dAT-CAFs showed a higher ability to induce the proliferation and in vivo metastasis of BCCs, which was involved in the activation of the transforming growth factor beta (TGFβ)-Smad2/3 signaling pathway. Collectively, our study suggests that T2DM contributes to metastasis of BCCs by inducing the myofibroblastic CAFs differentiation of dAT-MSCs. In addition, targeting the TGFβ-Smad2/3 signaling pathway in dAT-MSCs may be useful in cancer therapy for TNBC patients with T2DM.

Triple negative breast cancer (TNBC) is associated with worse outcomes and results in high mortality; therefore, great efforts are required to find effective treatment. In the present study, we suggested a novel strategy to treat TNBC using mesenchymal stem cell (MSC)-derived extracellular vesicles (EV) to transform the behaviors and cellular communication of TNBC cells (BCC) with other non-cancer cells related to tumorigenesis and metastasis. Our data showed that, BCC after being internalized with EV derived from Wharton's Jelly MSC (WJ-EV) showed the impaired proliferation, stemness properties, tumorigenesis and metastasis under hypoxic conditions. Moreover, these inhibitory effects may be involved in the transfer of miRNA-125b from WJ-EV to BCC, which downregulated the expression of HIF1α and target genes related to proliferation, epithelial-mesenchymal transition, and angiogenesis. Of note, WJ-EV-internalized BCC (wBCC) showed transformed behaviors that attenuated the in vivo development and metastatic ability of TNBC, the angiogenic abilities of endothelial cells and endothelial progenitor cells and the generation of cancer-associated fibroblasts from MSC. Furthermore, wBCC generated a new EV with modified functions that contributed to the inhibitory effects on tumorigenesis and metastasis of TNBC. Taken together, our findings suggested that WJ-EV treatment is a promising therapy that results in the generation of wBCC to interrupt the cellular crosstalk in the tumor environment and inhibit the tumor progression in TNBC.

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic has influenced antibiotic consumption over a long period, with variability in trends among studies. We conducted this systematic review to explore and compare the effect of the pandemic on overall and individual antibiotic consumption in 2020 with that in 2019.MethodsThis systematic literature review was conducted using PubMed, EMBASE, and Web of Science databases. Data on antibiotic consumption in Japan was sourced from the Japan Surveillance of Antimicrobial Consumption.ResultsA total of 1,442 articles and reports were screened, and 16 eligible articles were reviewed. The included studies were conducted in Jordan, Australia, Canada, UK, Japan, Brazil, India, China, and the EU. There was no study from African and Southeast Asian Countries. Overall, antibiotic consumption in the community consistently reduced in 2020. Studies from Australia, Canada, Portugal, Spain, the UK, Japan, and the European Union reported both decreases in overall and selected individual antibiotics consumption. In contrast, hospital-based studies reported both increases and decreases. Hospital-based studies in Lebanon, Spain, Italy, India, and the UK reported an increase in antibiotic consumption in 2020. Studies reporting an interruption of antibiotic stewardship programs during the pandemic also reported increases in antibiotic consumption for hospitalized patients in 2020 compared with that in 2019.ConclusionOur results showed a different trend between communities and hospitals in antibiotic consumption during 2020 compared to 2019. The continuity of the antibiotic stewardship program might have influenced the antibiotic consumption trend variability among hospitals in 2020. Alongside this, the lack of information on antibiotic consumption from low-income countries and limited reports from middle-income countries revealed gaps that need to be urgently filled.

Introduction: The therapeutic effects of endothelial progenitor cells (EPC) in neovascularization have been suggested; however, to date, few studies have been conducted on the ability of EPC-derived extracellular vesicles (EV) to rescue the ischemic tissues. In order to examine the functional sources of EV for cell-free therapy of ischemic diseases, we compared the functions of EPC-EV and those of Wharton's Jelly-derived mesenchymal stem cell (WJ-EV) in the flap mouse model. Results and conclusion: Our results demonstrated that in the intravenous injection, EPC-EV, but not WJ-EV, were uptaken by the ischemic tissues. However, EPC-EV showed poor abilities to induce neovascularization and the recovery of ischemic tissues. In addition, compared to EPC-EV, WJ-EV showed a higher ability to rescue the ischemic injury when being locally injected into the mice. In order to induce the secretion of high-functional EPC-EV, EPC were internalized with hypoxic pre-treated WJ-EV, which resulted in a transformed hwEPC. In comparison to EPC, hwEPC showed induced proliferation and upregulation of angiogenic genes and miRNAs and promoted angiogenic ability. Interestingly, hwEPC produced a modified EV (hwEPC-EV) that highly expressed miRNAs related to angiogenesis, such as miR-155, miR-183, and miR-296. Moreover, hwEPC-EV significantly induced the neovascularization of the ischemic tissues which were involved in promoting the proliferation, the expression of VEGF and miR-183, and the angiogenic functions of endothelial cells. Of note, hwEPC-EV were highly uptaken by the ischemic tissues and showed a greater effect with regard to inducing recovery from ischemic injury in the intravenous administration, compared to EPC-EV. Therefore, hwEPC-EV can be considered a functional candidate for cell-free therapy to treat the distal ischemic tissues.

Coronavirus disease 2019 (COVID-19) has spread faster due to the emergence of SARS-CoV-2 variants, which carry an increased risk of infecting patients with comorbidities, such as breast cancer. However, there are still few reports on the effects of SARS-CoV-2 infection on the progression of breast cancer, as well as the factors and mechanisms involved. In the present study, we investigated the impact of SARS-CoV-2 proteins on breast cancer cells (BCC). The results suggested that SARS-CoV-2 M protein induced the mobility, proliferation, stemness and in vivo metastasis of a triple-negative breast cancer (TNBC) cell line, MDA-MB-231, which are involved in the upregulation of NFκB and STAT3 pathways. In addition, compared to MDA-MB-231 cells, the hormone-dependent breast cancer cell line MCF-7 showed a less response to M protein, with the protein showing no effects of promoting proliferation, stemness, and in vivo metastasis. Of note, coculture with M protein-treated MDA-MB-231 cells significantly induced the migration, proliferation, and stemness of MCF-7 cells, which are involved in the upregulation of genes related to EMT and inflammatory cytokines. Therefore, SARS-CoV-2 infection might promote the ability of aggressive BCC to induce the malignant phenotypes of the other non-aggressive BCC. Taken together, these findings suggested an increased risk of poor outcomes in TNBC patients with a history of SARS-CoV-2 infection, which required a long-term follow-up. In addition, the inhibition of NFκB and STAT3 signaling pathways is considered as a promising candidate for the treatment of worsen clinical outcomes in TNBC patients with COVID-19.

The outbreak of the COVID-19 pandemic has had an unprecedented impact on humanity as well as research activities in life sciences and medicine. Between January and August 2020, the number of coronavirus-related scientific articles was roughly 50 times more than that of articles published in the entire year of 2019 in PubMed. It is necessary to better understand the dynamics of research on COVID-19, an emerging topic, and suggest ways to understand and improve the quality of research. We analyze the dynamics of coronavirus research before and after the outbreaks of SARS, MERS, and COVID-19 by examining all the published articles from the past 25 years in PubMed. We delineate research networks on coronaviruses as we identify experts’ background in terms of topics of previous research, affiliations, and international co-authorships. Two distinct dynamics of coronavirus research were found: 1) in the cases of regional pandemics, SARS and MERS, the scope of cross-disciplinary research remained between neighboring research areas; 2) in the case of the global pandemic, COVID-19, research activities have spread beyond neighboring disciplines with little transnational collaboration. Thus, COVID-19 has transformed the structure of research on coronaviruses as an emerging issue. Knowledge on COVID-19 is distributed across the widest range of disciplines, transforming research networks well beyond the field of medicine but within national boundaries. Given the unprecedented scale of COVID-19 and the nationalization of responses, the most likely way forward is to accumulate local knowledge with the awareness of transdisciplinary research dynamics.

Cytokine storm is recognized as one of the factors contributing to organ failures and mortality in patients with COVID-19. Due to chronic inflammation, COVID-19 patients with diabetes mellitus (DM) or renal disease (RD) have more severe symptoms and higher mortality. However, the factors that contribute to severe outcomes of COVID-19 patients with DM and RD have received little attention. In an effort to investigate potential treatments for COVID-19, recent research has focused on the immunomodulation functions of mesenchymal stem cells (MSCs). In this study, the correlation between DM and RD and the severity of COVID-19 was examined by a combined approach with a meta-analysis and experimental research. The results of a systematic review and meta-analysis suggested that the odd of mortality in patients with both DM and RD was increased in comparison to those with a single comorbidity. In addition, in the experimental research, the data showed that high glucose and uremic toxins contributed to the induction of cytokine storm in human lung adenocarcinoma epithelial cells (Calu-3 cells) in response to SARS-CoV Peptide Pools. Of note, the incorporation of Wharton's jelly MSC-derived extracellular vesicles (WJ-EVs) into SARS-CoV peptide-induced Calu-3 resulted in a significant decrease in nuclear NF-κB p65 and the downregulation of the cytokine storm under high concentrations of glucose and uremic toxins. This clearly suggests the potential for WJ-EVs to reduce cytokine storm reactions in patients with both chronic inflammation diseases and viral infection.

Cancer metastasis is the leading cause of mortality among breast cancer patients.Type 2 diabetes mellitus (T2DM) has been suggested as a risk factor of breast cancer; however, whether or not T2DM is associated with breast tumor metastasis remains unclear.In this study, we examined the involvement of T2DM with breast cancer metastasis by a combined approach of a meta-analysis and experimental research.The results of a systematic review and meta-analysis suggested that diabetes significantly increases the risk of lymph node metastasis by 1.10-fold (P < 0.01).Consistently, our data from experimental research showed that T2DM induced paracrine effects of mesenchymal stem cells (MSCs), a key contributor to cancer progression, to stimulate metastasis of breast cancer cells (BCCs) by two independent mechanisms.First, T2DM induced the excess secretion of interleukin 6 (IL6) from MSCs, which activated the JAK/STAT3 pathway in BCCs, thus promoting the metastasis of BCCs.Second, beside the EGR-1-/IL6-dependent mechanism, T2DM altered the functions of MSC-derived extracellular vesicles (EVs), which are highly associated with the metastasis of BCCs.Our present study showed that T2DM is a risk factor for breast cancer metastasis, and MSC-derived EVs might be useful for developing a novel anti-breast cancer therapy strategy.

Aging induces numerous cellular disorders, such as the elevation of reactive oxygen species (ROS), in a number type of cells, including mesenchymal stem cells (MSCs). However, the correlation of ROS and impaired healing abilities as well as whether or not the inhibition of elevating ROS results in the rejuvenation of elderly MSCs is unclear. The rejuvenation of aged MSCs has thus recently received attention in the field of regenerative medicine. Specifically, extracellular vesicles (EVs) act as a novel tool for stem cell rejuvenation due to their gene transfer ability with systemic effects and safety. In the present study, we examined the roles of aging-associated ROS in the function and rejuvenation of elderly MSCs by infant EVs. The data clearly showed that elderly MSCs exhibited the downregulation of superoxide dismutase (SOD)1 and SOD3, which resulted in the elevation of ROS and downregulation of the MEK/ERK pathways, which are involved in the impairment of the MSCs’ ability to decrease necrotic area in the skin flap model. Furthermore, treatment with the antioxidant Edaravone or co-overexpression of SOD1 and SOD3 rescued elderly MSCs from the elevation of ROS and cellular senescence, thereby improving their functions. Of note, infant MSC-derived EVs rejuvenated elderly MSCs by inhibiting ROS production and the acceleration of cellular senescence and promoting the proliferation and in vivo functions in both type 1 and type 2 diabetic mice.

Stem cells are one of the leading methods through which we will gain the next generation of medical treatments. Given their ability to develop into almost any cell type, the medical applications are endless. Since the methods through which to reprogramme these master progenitors were established, many tests and clinical trials have taken place. However, as is often the case in biology, the picture is more complicated than simply reprogramming these cells with a cocktail of proteins. Stem cell expert Professor Osamu Ohneda is a Principal Investigator at the University of Tsukuba, Japan. 'Our focus is to achieve autologous transplantation whereby, mesenchymal stem cells are taken from the patient, encouraged to grow and reprogrammed before transplantation into the patient,' he observes. This process would be a crucial step in the personalisation of medicine, however, the more this process has been tested, the clearer it has become that additional variables are in play. 'There have been issues with nearly every step of the process after the acquirement of the raw mesenchymal stem cells (MSCs) necessary,' Ohneda highlights. 'The MSCs don't always respond as expected to growth stimulants and differentiation cues and transplants don't always take.' More in depth research is needed to overcome these issues and turn stem cell's potential into a reality. Investigating and solving these issues is the work of Ohneda and his research team, including Assistant Professor Vuong Cat Khanh and Assistant Professor Toshiharu Yamashita.

Embryonic stem (ES) cells have been utilized as an excellent model for the study of neural development. However, the dynamic changes of ES cell-derived neural stem cells (ES-NSCs), under the effects of prolonged cell culture and hypoxic conditions, are still obscured. In the present study, using the combination of serum-free culture of embryoid body-like aggregates (SFEB) culture and cell sorting by Sox-1, the ES-NSCs were easily isolated and showed in vitro temporal neural specification, which resulted in distinct cell fates after neural differentiation. Early passaged ES-NSCs gave rise to neurons, whereas late-passaged ES-NSCs gave rise to glial cells, similar to the in vivo dynamic changes during the neural development. Remarkably, hypoxia treatment induced the neural differentiation of ES-NSCs but did not affect the cell fate. Under hypoxic conditions, early passaged ES-NSCs showed the upregulation of neuronal markers, whereas late-passaged ES-NSCs showed the upregulation of a glial marker. In addition, the knockdown of the hypoxia-inducible factor 1α expression impaired the neuronal differentiation of early passaged ES-NSCs under hypoxic conditions. These data demonstrated the distinct effects of prolonged culture and hypoxic stimuli on the neural differentiation of ES-NSCs; prolonged culture was involved in the cell fate after neural differentiation, while hypoxia treatment efficiently promoted neural differentiation.