Human Amniocytes Are Receptive to Chemically Induced Reprogramming to Pluripotency.

Restoring pluripotency using chemical compounds alone would be a major step forward in developing clinical-grade pluripotent stem cells, but this has not yet been reported in human cells. We previously demonstrated that VPA_AFS cells, human amniocytes cultivated with valproic acid (VPA) acquired functional pluripotency while remaining distinct from human embryonic stem cells (hESCs), questioning the relationship between the modulation of cell fate and molecular regulation of the pluripotency network. Here, we used single-cell analysis and functional assays to reveal that VPA treatment resulted in a homogeneous population of self-renewing non-transformed cells that fulfill the hallmarks of pluripotency, i.e., a short G1 phase, a dependence on glycolytic metabolism, expression of epigenetic modifications on histones 3 and 4, and reactivation of endogenous OCT4 and downstream targets at a lower level than that observed in hESCs. Mechanistic insights into the process of VPA-induced reprogramming revealed that it was dependent on OCT4 promoter activation, which was achieved independently of the PI3K (phosphatidylinositol 3-kinase)/AKT/mTOR (mammalian target of rapamycin) pathway or GSK3ß inhibition but was concomitant with the presence of acetylated histones H3K9 and H3K56, which promote pluripotency. Our data identify, for the first time, the pluripotent transcriptional and molecular signature and metabolic status of human chemically induced pluripotent stem cells.

Gendered health systems: evidence from low- and middle-income countries.

BACKGROUND: Gender is often neglected in health systems, yet health systems are not gender neutral. Within health systems research, gender analysis seeks to understand how gender power relations create inequities in access to resources, the distribution of labour and roles, social norms and values, and decision-making. This paper synthesises findings from nine studies focusing on four health systems domains, namely human resources, service delivery, governance and financing. It provides examples of how a gendered and/or intersectional gender approach can be applied by researchers in a range of low- and middle-income settings (Cambodia, Zimbabwe, Uganda, India, China, Nigeria and Tanzania) to issues across the health system and demonstrates that these types of analysis can uncover new and novel ways of viewing seemingly intractable problems. METHODS: The research used a combination of mixed, quantitative, qualitative and participatory methods, demonstrating the applicability of diverse research methods for gender and intersectional analysis. Within each study, the researchers adapted and applied a variety of gender and intersectional tools to assist with data collection and analysis, including different gender frameworks. Some researchers used participatory tools, such as photovoice and life histories, to prompt deeper and more personal reflections on gender norms from respondents, whereas others used conventional qualitative methods (in-depth interviews, focus group discussion). Findings from across the studies were reviewed and key themes were extracted and summarised. RESULTS: Five core themes that cut across the different projects were identified and are reported in this paper as follows: the intersection of gender with other social stratifiers; the importance of male involvement; the influence of gendered social norms on health system structures and processes; reliance on (often female) unpaid carers within the health system; and the role of gender within policy and practice. These themes indicate the relevance of and need for gender analysis within health systems research. CONCLUSION: The implications of the diverse examples of gender and health systems research highlighted indicate that policy-makers, health practitioners and others interested in enhancing health system research and delivery have solid grounds to advance their enquiry and that one-size-fits-all heath interventions that ignore gender and intersectionality dimensions require caution. It is essential that we build upon these insights in our efforts and commitment to move towards greater equity both locally and globally.

Psychosocial adjustment and quality of life in children undergoing screening in a specialist paediatric hypertrophic cardiomyopathy clinic.

OBJECTIVE: This study aimed to assess the psychological well-being and quality of life in children with hypertrophic cardiomyopathy and the potential psychosocial impact of screening. METHODS: A total of 152 children (aged 3-18 years) attending a specialist paediatric hypertrophic cardiomyopathy clinic, and their parents completed the Generic Core Scales and Cardiac Module of the Paediatric Quality of Life Inventory (PedsQL) questionnaire as well as the Strengths and Difficulties Questionnaire; 21 patients (14%) had hypertrophic cardiomyopathy (group A); 23 children (15%) harboured hypertrophic cardiomyopathy-causing sarcomeric mutations with normal echocardiograms (group G); and 108 children (71%) had a family history of hypertrophic cardiomyopathy with normal investigations and attended for clinical cardiological screening (group S). RESULTS: In group A, mean PedsQLTM total scores reported by children and parents were lower than those reported by unaffected children (p<0.001). There was no significant difference between unaffected and gene-positive patients. Mean Cardiac module PedsQLTM total scores by children and parents were lower in children with hypertrophic cardiomyopathy compared with unaffected patients [mean child-reported total score 86.4 in group S versus 72.3 in group A (p<0.001) and 80.2 in group G (p=0.25); mean parent-reported total score 91.6 in group S versus 71.4 in group A (p<0.001) and 87 in group G (p=0.4)]. There was no significant difference between group S and group G on any of the scales, or between the three groups of patients in the mean Strengths and Difficulties Questionnaire scores. CONCLUSIONS: Children with hypertrophic cardiomyopathy have a significantly reduced quality of life. Importantly, Quality-of-Life scores among unaffected children attending for screening were not different compared with scores from a normative UK population.

Novel cell lines isolated from mouse embryonic stem cells exhibiting de novo methylation of the E-cadherin promoter.

Mouse embryonic stem cells (mESCs) and epiblast stem cells represent the naïve and primed pluripotent states, respectively. These cells self-renew via distinct signaling pathways and can transition between the two states in the presence of appropriate growth factors. Manipulation of signaling pathways has therefore allowed the isolation of novel pluripotent cell types such as Fibroblast growth factor, Activin and BIO-derived stem cells and IESCs. However, the effect of cell seeding density on pluripotency remains unexplored. In this study, we have examined whether mESCs can epigenetically regulate E-cadherin to enter a primed-like state in response to low cell seeding density. We show that low density seeding in the absence of leukaemia inhibitory factor (LIF) induces decreased apoptosis and maintenance of pluripotency via Activin/Nodal, concomitant with loss of E-cadherin, Signal transducer and activator of transcription phosphorylation, and chimera-forming ability. These cells, E-cadherin negative proliferating stem cells (ENPSCs) can be reverted to a naïve phenotype by addition of LIF or forced E-cadherin expression. However, prolonged culture of ENPSCs without LIF leads to methylation of the E-cadherin promoter (ENPSC(M)), which cannot be reversed by LIF supplementation, and increased histone H3K27 and decreased H3K4 trimethylation. Transcript analysis of ENPSC(M) revealed a primed-like phenotype and their differentiation leads to enrichment of neuroectoderm cells. The generation of ENPSCs is similar to tumorigenesis as ENPSCs exhibit transcript alterations associated with neoplasia, hyperplasia, carcinoma, and metastasis. We therefore describe a novel cell model to elucidate the role of E-cadherin in pluripotency and to investigate epigenetic regulation of this gene during mESC differentiation and tumor metastasis.

Snap shots from a photo competition: what does it reveal about close-to-community providers, gender and power in health systems?

In this commentary, we discuss a photography competition, launched during the summer of 2014, to explore the everyday stories of how gender plays out within health systems around the world. While no submission fees were charged nor financial awards involved, the winning entries were exhibited at the Global Symposium on Health Systems Research in Cape Town, South Africa, in October 2014, with credits to the photographers involved. Anyone who had an experience of, or interest in, gender and health systems was invited to participate. Underlying the aims of the photo competition was a recognition of the importance of participation of community members, health workers and other non-academics in our research engagement and in venues where their perspectives are often missing. The competition elicited participation from a range of stakeholders engaged in health systems: professional photographers, project managers, donors, researchers, activists and community members. In total, 54 photos were submitted by 29 participants from 15 different nationalities and country locations. We unpack what the photos suggest about gender and health systems and the pivotal role of community-level systems that support health, including that of close-to-community health providers. Three themes emerged: women active on the frontlines of service delivery and as primary unpaid carers, the visibility of men in gender and health systems and the inter-sectoral nature and intra-household dynamics of community health that embed close-to-community health providers. The question of who has the right to take and display images, under what contexts and for what purpose also permeated the photo competition. We reflect on how photos can be valuable representations of the worlds that we, health workers and health systems are embedded in. Photographs broaden our horizons by capturing and connecting us to subjects from afar in seemingly unmediated ways but also reflect the politics, values and subjectivities of the photographer. They represent stereotypes, but also showcase alternate realities of people and health systems, and thereby can engender further reflection and change. We conclude with thoughts about the place of photography in health systems research and practice in highlighting and potentially transforming how we look at and address close-to-community providers.

E-cadherin and, in its absence, N-cadherin promotes Nanog expression in mouse embryonic stem cells via STAT3 phosphorylation.

We have recently shown that loss of E-cadherin in mouse embryonic stem cells (mESCs) results in significant alterations to both the transcriptome and hierarchy of pluripotency-associated signaling pathways. Here, we show that E-cadherin promotes kruppel-like factor 4 (Klf4) and Nanog transcript and protein expression in mESCs via STAT3 phosphorylation and that ß-catenin, and its binding region in E-cadherin, is required for this function. To further investigate the role of E-cadherin in leukemia inhibitory factor (LIF)-dependent pluripotency, E-cadherin null (Ecad(-/-)) mESCs were cultured in LIF/bone morphogenetic protein supplemented medium. Under these conditions, Ecad(-/-) mESCs exhibited partial restoration of cell-cell contact and STAT3 phosphorylation and upregulated Klf4, Nanog, and N-cadherin transcripts and protein. Abrogation of N-cadherin using an inhibitory peptide caused loss of phospho STAT3, Klf4, and Nanog in these cells, demonstrating that N-cadherin supports LIF-dependent pluripotency in this context. We therefore identify a novel molecular mechanism linking E- and N-cadherin to the core circuitry of pluripotency in mESCs. This mechanism may explain the recently documented role of E-cadherin in efficient induced pluripotent stem cell reprogramming.

Women healthcare workers' experiences during COVID-19 and other crises: A scoping review.

BACKGROUND: Throughout the COVID-19 pandemic, as measures have been taken to both prevent the spread of COVID-19 and provide care to those who fall ill, healthcare workers have faced added risks to their health and wellbeing. These risks are disproportionately felt by women healthcare workers, yet health policies do not always take a gendered approach. OBJECTIVES: The objective of this review was to identify the gendered effects of crises on women healthcare workers' health and wellbeing, as well as to provide guidance for decision-makers on health systems policies and programs that could better support women healthcare workers. METHODS: A scoping review of published academic literature was conducted. PubMed, EMBASE, and CINAHL were searched using combinations of relevant medical subject headings and keywords. Data was extracted using a thematic coding framework. Seventy-six articles met the inclusion criteria. RESULTS: During disease outbreaks women healthcare workers were found to experience: a higher risk of exposure and infection; barriers to accessing personal protective equipment; increased workloads; decreased leadership and decision-making opportunities; increased caregiving responsibilities in the home when schools and childcare supports were restricted; and higher rates of mental ill-health, including depression, anxiety, and post-traumatic stress disorder. There was a lack of attention paid to gender and the health workforce during times of crisis prior to COVID-19, and there is a substantial gap in research around the experiences of women healthcare workers in low- and middle-income countries during times of crises. CONCLUSION: COVID-19 provides an opportunity to develop gender-responsive crisis preparedness plans within the health sector. Without consideration of gender, crises will continue to exacerbate existing gender disparities, resulting in disproportionate negative impacts on women healthcare workers. The findings point to several important recommendations to better support women healthcare workers, including: workplace mental health support, economic assistance to counteract widening pay gaps, strategies to support their personal caregiving duties, and interventions that support and advance women's careers and increase their representation in leadership roles.

'Forgotten as first line providers': The experiences of midwives during the COVID-19 pandemic in British Columbia, Canada.

OBJECTIVE: To explore midwives' experiences working on the frontlines of the COVID-19 pandemic in British Columbia, Canada. DESIGN: Qualitative study involving three semi-structured focus groups and four in-depth interviews with midwives. SETTING: The COVID-19 pandemic in British Columbia, Canada from 2020-2021. PARTICIPANTS: 13 midwives working during the first year of the COVID-19 pandemic in British Columbia. FINDINGS: Qualitative analysis surfaced four key themes. First, midwives faced a substantial lack of support during the pandemic. Second, insufficient support was compounded by a lack of recognition. Third, participants felt a strong duty to continue providing high-quality care despite COVID-19 related restrictions and challenges. Lastly, lack of support, increased workloads, and moral distress exacerbated burnout among midwives and raised concerns around the sustainability of their profession. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Lack of effective support for midwives during the initial months of the COVID-19 pandemic exacerbated staffing shortages that existed prior to the pandemic, creating detrimental gaps in essential care for pregnant people, especially with increasing demands for homebirths. Measures to support midwives should combat inequities in the healthcare system, mitigating the risks of disease exposure, burnout, and professional and financial impacts that may have long-lasting implications on the profession. Given the crucial role of midwives in women- and people-centred care and advocacy, protecting midwives and the communities they serve should be prioritized and integrated into pandemic preparedness and response planning to preserve women's health and rights around the world.

Supporting community health workers in fragile settings from a gender perspective: a qualitative study.

OBJECTIVE: To explore how gender influences the way community health workers (CHWs) are managed and supported and the effects on their work experiences. SETTING: Two districts in three fragile countries. Sierra Leone-Kenema and Bonthe districts; Liberia-two districts in Grand Bassa county one with international support for CHW activities and one without: Democratic Republic of Congo (DRC)-Aru and Bunia districts in Ituri Province. PARTICIPANTS AND METHODS: Qualitative interviews with decision-makers and managers working in community health programmes and managing CHWs (n=36); life history interviews and photovoice with CHWs (n=15, in Sierra Leone only). RESULTS: While policies were put in place in Sierra Leone and Liberia to attract women to the newly paid position of CHW after the Ebola outbreak, these good intentions evaporated in practice. Gender norms at the community level, literacy levels and patriarchal expectations surrounding paid work meant that fewer women than imagined took up the role. Only in DRC, there were more women than men working as CHWs. Gender roles, norms and expectations in all contexts also affected retention and progression as well as safety, security and travel (over long distance and at night). Women CHWs also juggle between household and childcare responsibilities. Despite this, they were more likely to retain their position while men were more likely to leave and seek better paid employment. CHWs demonstrated agency in negotiating and challenging gender norms within their work and interactions supporting families. CONCLUSIONS: Gender roles and relations shape CHW experiences across multiple levels of the health system. Health systems need to develop gender transformative human resource management strategies to address gender inequities and restrictive gender norms for this critical interface cadre.

Health systems resilience in fragile and shock-prone settings through the prism of gender equity and justice: implications for research, policy and practice.

Fragile and shock-prone settings (FASP) present a critical development challenge, eroding efforts to build healthy, sustainable and equitable societies. Power relations and inequities experienced by people because of social markers, e.g., gender, age, education, ethnicity, and race, intersect leading to poverty and associated health challenges. Concurrent to the growing body of literature exploring the impact of these intersecting axes of inequity in FASP settings, there is a need to identify actions promoting gender, equity, and justice (GEJ). Gender norms that emphasise toxic masculinity, patriarchy, societal control over women and lack of justice are unfortunately common throughout the world and are exacerbated in FASP settings. It is critical that health policies in FASP settings consider GEJ and include strategies that promote progressive changes in power relationships. ReBUILD for Resilience (ReBUILD) focuses on health systems resilience in FASP settings and is underpinned by a conceptual framework that is grounded in a broader view of health systems as complex adaptive systems. The framework identifies links between different capacities and enables identification of feedback loops which can drive or inhibit the emergence and implementation of resilient approaches. We applied the framework to four different country case studies (Lebanon, Myanmar, Nepal and Sierra Leone) to illustrate how it can be inclusive of GEJ concerns, to inform future research and support context responsive recommendations to build equitable and inclusive health systems in FASP settings.

Can rights stop the wrongs? Exploring the connections between framings of sex workers' rights and sexual and reproductive health.

BACKGROUND: There is growing interest in the ways in which legal and human rights issues related to sex work affect sex workers' vulnerability to HIV and abuses including human trafficking and sexual exploitation. International agencies, such as UNAIDS, have called for decriminalisation of sex work because the delivery of sexual and reproductive health services is affected by criminalisation and social exclusion as experienced by sex workers. The paper reflects on the connections in various actors' framings between sex workers sexual and reproductive health and rights (SRHR) and the ways that international law is interpreted in policing and regulatory practices. METHODS: The literature review that informs this paper was carried out by the authors in the course of their work within the Paulo Longo Research Initiative. The review covered academic and grey literature such as resources generated by sex worker rights activists, UN policy positions and print and online media. The argument in this paper has been developed reflectively through long term involvement with key actors in the field of sex workers' rights. RESULTS: International legislation characterises sex work in various ways which do not always accord with moves toward decriminalisation. Law, policy and regulation at national level and law enforcement vary between settings. The demands of sex worker rights activists do relate to sexual and reproductive health but they place greater emphasis on efforts to remove the structural barriers that limit sex workers' ability to participate in society on an equal footing with other citizens. DISCUSSION AND CONCLUSION: There is a tension between those who wish to uphold the rights of sex workers in order to reduce vulnerability to ill-health and those who insist that sex work is itself a violation of rights. This is reflected in contemporary narratives about sex workers' rights and the ways in which different actors interpret human rights law. The creation of regulatory frameworks around sex work that support health, safety and freedom from abuse requires a better understanding of the broad scope of laws, policies and enforcement practices in different cultural contexts and economic settings, alongside reviews of UN policies and human rights conventions.

Strengthening the research to policy and practice interface: exploring strategies used by research organisations working on sexual and reproductive health and HIV/AIDS.

This commentary introduces the HARPS supplement on getting research into policy and practice in sexual and reproductive health (SRH). The papers in this supplement have been produced by the Sexual Health and HIV Evidence into Practice (SHHEP) collaboration of international research, practitioner and advocacy organizations based in research programmes funded by the UK Department for International Development.The commentary describes the increasing interest from research and communication practitioners, policy makers and funders in expanding the impact of research on policy and practice. It notes the need for contextually embedded understanding of ways to engage multiple stakeholders in the politicized, sensitive and often contested arenas of sexual and reproductive health. The commentary then introduces the papers under their respective themes: (1) The theory and practice of research engagement (two global papers); (2) Applying policy analysis to explore the role of research evidence in SRH and HIV/AIDS policy (two papers with examples from Ghana, Malawi, Uganda and Zambia); (3) Strategies and methodologies for engagement (five papers on Kenya, South Africa, Ghana, Tanzania and Swaziland respectively); (4) Advocacy and engagement to influence attitudes on controversial elements of sexual health (two papers, Bangladesh and global); and (5) Institutional approaches to inter-sectoral engagement for action and strengthening research communications (two papers, Ghana and global).The papers illustrate the many forms research impact can take in the field of sexual and reproductive health. This includes discursive changes through carving out legitimate spaces for public debate; content changes such as contributing to changing laws and practices, procedural changes such as influencing how data on SRH are collected, and behavioural changes through partnerships with civil society actors such as advocacy groups and journalists.The contributions to this supplement provide a body of critical analysis of communication and engagement strategies across the spectrum of SRH and HIV/AIDS research through the testing of different models for the research-to-policy interface. They provide new insights on how researchers and communication specialists can respond to changing policy climates to create windows of opportunity for influence.

Publisher Correction: Human mid-trimester amniotic fluid (stem) cells lack expression of the pluripotency marker OCT4A.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

How to prevent and address safeguarding concerns in global health research programmes: practice, process and positionality in marginalised spaces.

Safeguarding is rapidly rising up the international development agenda, yet literature on safeguarding in related research is limited. This paper shares processes and practice relating to safeguarding within an international research consortium (the ARISE hub, known as ARISE). ARISE aims to enhance accountability and improve the health and well-being of marginalised people living and working in informal urban spaces in low-income and middle-income countries (Bangladesh, India, Kenya and Sierra Leone). Our manuscript is divided into three key sections. We start by discussing the importance of safeguarding in global health research and consider how thinking about vulnerability as a relational concept (shaped by unequal power relations and structural violence) can help locate fluid and context specific safeguarding risks within broader social systems. We then discuss the different steps undertaken in ARISE to develop a shared approach to safeguarding: sharing institutional guidelines and practice; facilitating a participatory process to agree a working definition of safeguarding and joint understandings of vulnerabilities, risks and mitigation strategies and share experiences; developing action plans for safeguarding. This is followed by reflection on our key learnings including how safeguarding, ethics and health and safety concerns overlap; the challenges of referral and support for safeguarding concerns within frequently underserved informal urban spaces; and the importance of reflective practice and critical thinking about power, judgement and positionality and the ownership of the global narrative surrounding safeguarding. We finish by situating our learning within debates on decolonising science and argue for the importance of an iterative, ongoing learning journey that is critical, reflective and inclusive of vulnerable people.

Modelling mitochondrial dysfunction in Alzheimer's disease using human induced pluripotent stem cells.

Alzheimer's disease (AD) is the most common form of dementia. To date, only five pharmacological agents have been approved by the Food and Drug Administration for clinical use in AD, all of which target the symptoms of the disease rather than the cause. Increasing our understanding of the underlying pathophysiology of AD will facilitate the development of new therapeutic strategies. Over the years, the major hypotheses of AD etiology have focused on deposition of amyloid beta and mitochondrial dysfunction. In this review we highlight the potential of experimental model systems based on human induced pluripotent stem cells (iPSCs) to provide novel insights into the cellular pathophysiology underlying neurodegeneration in AD. Whilst Down syndrome and familial AD iPSC models faithfully reproduce features of AD such as accumulation of Aß and tau, oxidative stress and mitochondrial dysfunction, sporadic AD is much more difficult to model in this way due to its complex etiology. Nevertheless, iPSC-based modelling of AD has provided invaluable insights into the underlying pathophysiology of the disease, and has a huge potential for use as a platform for drug discovery.

Local ownership of health policy and systems research in low-income and middle-income countries: a missing element in the uptake debate.

Health policy and systems researchers (HPSRs) in low-income and middle-income countries (LMICs) aim to influence health systems planning, costing, policy and implementation. Yet, there is still much that we do not know about the types of health systems evidence that are most compelling and impactful to policymakers and community groups, the factors that facilitate the research to decision-making process and the real-world challenges faced when translating research findings into practice in different contexts. Drawing on an analysis of HPSR from LMICs presented at the Fifth Global Symposium on Health Systems Research (HSR 2018), we argue that while there is a recognition in policy studies more broadly about the role of co-production, collective ownership and the value of localised HPSR in the evidence-to-policy discussion, 'ownership' of research at country level is a research uptake catalyst that needs to be further emphasised, particularly in the HPSR context. We consider embedded research, participatory or community-initiated research and emergent/responsive research processes, all of which are 'owned' by policymakers, healthcare practitioners/managers or community members. We embrace the view that ownership of HPSR by people directly affected by health problems connects research and decision-making in a tangible way, creating pathways to impact.

Human mid-trimester amniotic fluid (stem) cells lack expression of the pluripotency marker OCT4A.

Expression of OCT4A is one of the hallmarks of pluripotency, defined as a stem cell's ability to differentiate into all the lineages of the three germ layers. Despite being defined as non-tumorigenic cells with high translational potential, human mid-trimester amniotic fluid stem cells (hAFSCs) are often described as sharing features with embryonic stem cells, including the expression of OCT4A, which could hinder their clinical potential. To clarify the OCT4A status of hAFSCs, we first undertook a systematic review of the literature. We then performed extensive gene and protein expression analyses to discover that neither frozen, nor fresh hAFSCs cultivated in multipotent stem cell culture conditions expressed OCT4A, and that the OCT4A positive results from the literature are likely to be attributed to the expression of pseudogenes or other OCT4 variants. To address this issue, we provide a robust protocol for the assessment of OCT4A in other stem cells.

Neuroprotection of the hypoxic-ischemic mouse brain by human CD117+CD90+CD105+ amniotic fluid stem cells.

Human amniotic fluid contains two morphologically-distinct sub-populations of stem cells with regenerative potential, spindle-shaped (SS-hAFSCs) and round-shaped human amniotic fluid stem cells (RS-hAFSCs). However, it is unclear whether morphological differences correlate with functionality, and this lack of knowledge limits their translational applications. Here, we show that SS-hAFSCs and RS-hAFSCs differ in their neuro-protective ability, demonstrating that a single contralateral injection of SS-hAFSCs into hypoxic-ischemic P7 mice conferred a 47% reduction in hippocampal tissue loss and 43-45% reduction in TUNEL-positive cells in the hippocampus and striatum 48 hours after the insult, decreased microglial activation and TGFß1 levels, and prevented demyelination. On the other hand, RS-hAFSCs failed to show such neuro-protective effects. It is possible that SS-hAFSCs exert their neuroprotection via endoglin-dependent inhibition of TGFß1 signaling in target cells. These findings identify a sub-population of CD117+CD90+CD105+ stem cells as a promising source for the neuro-protection of the developing brain.

Embryonic Stem Cell-Derived Mesenchymal Stem Cells (MSCs) Have a Superior Neuroprotective Capacity Over Fetal MSCs in the Hypoxic-Ischemic Mouse Brain.

Human mesenchymal stem cells (MSCs) have huge potential for regenerative medicine. In particular, the use of pluripotent stem cell-derived mesenchymal stem cells (PSC-MSCs) overcomes the hurdle of replicative senescence associated with the in vitro expansion of primary cells and has increased therapeutic benefits in comparison to the use of various adult sources of MSCs in a wide range of animal disease models. On the other hand, fetal MSCs exhibit faster growth kinetics and possess longer telomeres and a wider differentiation potential than adult MSCs. Here, for the first time, we compare the therapeutic potential of PSC-MSCs (ES-MSCs from embryonic stem cells) to fetal MSCs (AF-MSCs from the amniotic fluid), demonstrating that ES-MSCs have a superior neuroprotective potential over AF-MSCs in the mouse brain following hypoxia-ischemia. Further, we demonstrate that nuclear factor (NF)-κB-stimulated interleukin (IL)-13 production contributes to an increased in vitro anti-inflammatory potential of ES-MSC-conditioned medium (CM) over AF-MSC-CM, thus suggesting a potential mechanism for this observation. Moreover, we show that induced pluripotent stem cell-derived MSCs (iMSCs) exhibit many similarities to ES-MSCs, including enhanced NF-κB signaling and IL-13 production in comparison to AF-MSCs. Future studies should assess whether iMSCs also exhibit similar neuroprotective potential to ES-MSCs, thus presenting a potential strategy to overcome the ethical issues associated with the use of embryonic stem cells and providing a potential source of cells for autologous use against neonatal hypoxic-ischemic encephalopathy in humans. Stem Cells Translational Medicine 2018;7:439-449.