New therapeutic approaches of mesenchymal stem cells-derived exosomes.

Mesenchymal stem cells (MSCs) have been demonstrated to have a great potential in the treatment of several diseases due to their differentiation and immunomodulatory capabilities and their ability to be easily cultured and manipulated. Recent investigations revealed that their therapeutic effect is largely mediated by the secretion of paracrine factors including exosomes. Exosomes reflect biophysical features of MSCs and are considered more effective than MSCs themselves. Alternative approaches based on MSC-derived exosomes can offer appreciable promise in overcoming the limitations and practical challenges observed in cell-based therapy. Furthermore, MSC-derived exosomes may provide a potent therapeutic strategy for various diseases and are promising candidates for cell-based and cell-free regenerative medicine. This review briefly summarizes the development of MSCs as a treatment for human diseases as well as describes our current knowledge about exosomes: their biogenesis and molecular composition, and how they exert their effects on target cells. Particularly, the therapeutic potential of MSC-derived exosomes in experimental models and recent clinical trials to evaluate their safety and efficacy are summarized in this study. Overall, this paper provides a current overview of exosomes as a new cell-free therapeutic agent.

Neurotrophic Factors Secreted by Induced Pluripotent Stem Cell-Derived Retinal Progenitors Promote Retinal Survival and Preservation in an Adult Porcine Neuroretina Model.

Purpose: Paracrine factors released by pluripotent stem cells have shown great potential as therapeutic agents in regenerative medicine. The purpose of this study was to characterize trophic factor secretion of retinal progenitor cells (RPCs) derived from human induced pluripotent stem cells (iPSCs) and to assess its impact on retinal survival ex vivo. Methods: RPCs were generated from human 3D1 iPSCs following previously established protocols with modifications. Conditioned medium (CM) was harvested from iPSC-derived retinal progenitors and analyzed for trophic factor composition through multiplex enzyme-linked immunosorbent assay. Retina-preserving capability of the collected CM was examined using a degenerative porcine neuroretina model. Viability of the CM-treated retina explants was evaluated using the resazurin-based PrestoBlue reagent, whereas the lactate dehydrogenase (LDH) assay was used to assess retinal cytotoxicity. Retina explants were also analyzed morphologically through immunohistochemistry for glial cell activation and apoptosis. Results: We have successfully generated and characterized iPSC-derived RPCs that secreted an array of neuroprotective factors, including osteopontin, hepatocyte growth factor, stromal cell-derived factor 1, and insulin-like growth factor-1. Retina explants cultured in CM derived from iPSC-RPCs (iPSC-RPC-CM) showed better preservation of the retinal microarchitecture and fewer terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)+ nuclei, and reduced reactive gliosis. Furthermore, we saw a reduction in extracellular LDH levels in CM-treated retina explants, which also exhibited higher metabolic activity than the untreated controls. Conclusions: iPSC-derived RPCs secrete many trophic factors that have been shown to promote neuroprotection, tissue repair, and regeneration in the retina. Overall, we have demonstrated the neuroprotective effects of iPSC-RPC-CM through a degenerative neuroretina model ex vivo.

Cell and gene therapy manufacturing capabilities in Australia and New Zealand.

Cell and gene therapy products are rapidly being integrated into mainstream medicine. Developing global capability will facilitate broad access to these novel therapeutics. An initial step toward achieving this goal is to understand cell and gene therapy manufacturing capability in each region. We conducted an academic survey in 2018 to assess cell and gene therapy manufacturing capacity in Australia and New Zealand. We examined the following: the number and types of cell therapy manufacturing facilities; the number of projects, parallel processes and clinical trials; the types of products; and the manufacturing and quality staffing levels. It was found that Australia and New Zealand provide diverse facilities for cell therapy manufacturing, infrastructure and capability. Further investment and development will enable both countries to make important decisions to meet the growing need for cell and gene therapy and regenerative medicine in the region.

Systematic review of controlled clinical studies using umbilical cord blood for regenerative therapy: Identifying barriers to assessing efficacy.

Clinical use of umbilical cord blood (UCB) for novel indications in regenerative therapy continues to rise, however, whether new indications are proven is less clear. An updated systematic search of the literature, focusing only on controlled clinical studies, is needed to properly assess potential efficacy. After updating our systematic search to April 1, 2018 (PROSPERO protocol CRD42016040157), a total of 16 studies were identified that addressed the treatment of cerebral palsy (four studies), type 1 diabetes (three studies), and nine other novel potential indications where only a single controlled study was identified. In the four controlled studies of patients with cerebral palsy, three used allogeneic cells and reported greater improvement in motor-related scores at 1, 3 and 6 months compared with controls. The results were mixed for other scores at other time points, including additional measures of mental and motor function. One study of autologous UCB treatment reported an improvement in motor function scores at 12 months compared with controls. In the three controlled studies of type 1 diabetes, two studies used autologous cells whereas one used allogeneic cord blood cells to "educate" autologous lymphocytes. Taken together, there was no clear difference in HbA1c levels or daily insulin requirements between treated patients and controls. For the nine published reports with a single controlled study, eight used allogeneic UCB cells and seven infused mesenchymal stromal cells derived from UCB. All but one study reported benefit. Many other published reports that lack a control group were not included in our analysis. More controlled studies are needed that use similar approaches regarding cell source and outcome measures at similar time points. Pooled estimates of results from multiple studies will be essential as published studies remain modest in size. Patients should continue to be enrolled in clinical trials because there are no novel potential indications remain unproven.

Establishment of the National Consortium for Regenerative Medicine and National Regenerative Medicine Database in Japan.

With its aim to regain the function of organs that are damaged by illness or injury, regenerative medicine has become the global focus of research. To accelerate the development and establishment of sufficient safety measures in regenerative medicine in Japan, the Pharmaceuticals and Medical Devices Act and the Act on Safety of Regenerative Medicine were enacted in 2014. Advancements in regenerative medicine are anticipated to draw attention toward the development of a system that consolidates and uses valuable data from studies performed from premarketing to postmarketing stages. Data gathered from premarketing to postmarketing stages of clinical research would promote new development avenues that would lead to the establishment of appropriate evaluation methods for new regenerative medical products by data validation. Against this background, the Japanese Society for Regenerative Medicine has been working to establish a national consortium for promoting regenerative medicine and constructing a large-scale clinical data registry, called the National Regenerative Medicine Database. This article aims to introduce the current framework of regenerative medicine in Japan, with a particular focus on the activity for establishment of a national consortium for regenerative medicine and the National Regenerative Medicine Database.

Stem Cells for the Treatment of Knee Osteoarthritis: A Comprehensive Review.

BACKGROUND: Knee osteoarthritis (KOA) is a very challenging condition to treat and can be resistant to medications, procedures, and even surgery. Surgery may not be an option for some patients due to obesity or comorbidities. Regenerative medicine utilizing stem cells, platelet rich plasma (PRP), amniotic fluid, and cytokine modulation is very promising in the treatment of KOA. OBJECTIVE: This is a review article to evaluate the current evidence about regenerative medicine therapies in the treatment of KOA. STUDY DESIGN: A review article. SETTING: A review of literature. METHODS: An online search of PubMed and Cochrane Library databases between January 2006 and December 2016 was performed to search related articles using the keywords of "treatment, stem cell, knee osteoarthritis," limited to the English language. The articles were then screened to make sure only articles fitting our inclusion criteria were included. RESULTS: Our search obtained a total of 268 articles, but only 18 articles met the inclusion criteria and were included in the current study. LIMITATIONS: There is still limited evidence in literature about the efficacy of regenerative medicine in treating KOA. More large clinical trials are needed to confirm the evidence. CONCLUSION: The present investigation demonstrates that regenerative medicine technologies provide good evidence in the treatment of osteoarthritis (OA) of the knee, but greater in-depth study to explore a more ideal way to overcome present difficulties, including standardization of sources of cells, is warranted. KEY WORDS: Knee osteoarthritis, stem cell, treatment, platelet rich plasma, amniotic fluid, articular cartilage defect.

A Comparative Analysis of Attitudes on Communication Toward Stem Cell Research and Regenerative Medicine Between the Public and the Scientific Community.

Owing to the rapid progress in stem cell research (SCR) and regenerative medicine (RM), society's expectation and interest in these fields are increasing. For effective communication on issues concerning SCR and RM, surveys for understanding the interests of stakeholders is essential. For this purpose, we conducted a large-scale survey with 2,160 public responses and 1,115 responses from the member of the Japanese Society for Regenerative Medicine. Results showed that the public is more interested in the post-realization aspects of RM, such as cost of care, countermeasures for risks and accidents, and clarification of responsibility and liability, than in the scientific aspects; the latter is of greater interest only to scientists. Our data indicate that an increased awareness about RM-associated social responsibility and regulatory framework is required among scientists, such as those regarding its benefits, potential accidents, abuse, and other social consequences. Awareness regarding the importance of communication and education for scientists are critical to bridge the gaps in the interests of the public and scientists. Stem Cells Translational Medicine 2018;7:251-257.

How to build an allogeneic hematopoietic cell transplant unit in 2016: Proposal for a practical framework.

Allogeneic hematopoietic cell transplantation is part of the standard of care for many hematological diseases. Over the last decades, significant advances in patient and donor selection, conditioning regimens as well as supportive care of patients undergoing allogeneic hematopoietic cell transplantation leading to improved overall survival have been made. In view of many new treatment options in cellular and molecular targeted therapies, the place of allogeneic transplantation in therapy concepts must be reviewed. Most aspects of hematopoietic cell transplantation are well standardized by national guidelines or laws as well as by certification labels such as FACT-JACIE. However, the requirements for the construction and layout of a unit treating patients during the acute phase of the transplantation procedure or at readmission for different complications are not well defined. In addition, the infrastructure of such a unit may be decisive for optimized care of these fragile patients. Here we describe the process of planning a transplant unit in order to open a discussion that could lead to more precise guidelines in the field of infrastructural requirements for hospitals caring for people with severe immunosuppression.

Stem cell industry update: 2012 to 2016 reveals accelerated investment, but market capitalization and earnings lag.

Treatments based on stem cells have long been heralded for their potential to drive the future of regenerative medicine and have inspired increasing medical and business interest. The stem cell therapy market has been expanding since 2012, but earnings and profitability still lag the broader health care sector (compounded annual growth rate in annual financing of 31.5% versus 13.4%, respectively). On the basis of historical financial data, approximately $23 billion has been invested in stem cell companies since 1994, with more than 80% of this raised from 2011 through 2016. This reflects a marked acceleration in capital investment, as companies began late-stage clinical trials, initiate partnerships or are acquired by large pharmaceutical companies. All of these data reflect a field that is emerging from infancy, which will demand more time and capital to mature. This update is relevant to researchers, clinicians and investors who wish to quantify the potential in this field.

Provider Perceptions of Treatment Options for Immature Permanent Teeth.

INTRODUCTION: Current treatment options for immature permanent teeth with pulpal necrosis include both apexification and regenerative endodontics. The purpose of this study was to survey endodontists on the use of these 2 treatment options. METHODS: Surveys were created by using Qualtrics and Teleform software and distributed by using the Salant and Dillman method. Endodontists (n = 1615) in 4 geographically and demographically diverse states, North Carolina, New York, Texas, and California, were surveyed. Data were analyzed by using descriptive statistics and χ2 analysis. Level of significance was set at 0.05. RESULTS: A 32.9% response rate was obtained. The majority of responders reported that apexification was the treatment of choice when considering the evidence base supporting the treatment (60%) and the predictability of treatment outcome (77.8%). Apexification was also the preferred treatment by 57.3% of respondents when asked to consider patient compliance, by 51.2% when considering the number of required patient appointments, and by 53.3% when considering the likelihood of tooth discoloration. Regenerative endodontics was reported as the preferred treatment by 89% of respondents when considering continued root development and by 66.7% when considering apical closure. The respondents' age and continuing education courses taken were significantly associated with their preferred treatment option. CONCLUSIONS: The results of our study indicate that endodontists consider both clinical and patient factors when treating immature teeth with pulpal necrosis. Increase in continuing education options may increase adoption of regenerative endodontic therapy.

Prevalence of Medical Conditions Potentially Amenable to Cellular Therapy among Families Privately Storing Umbilical Cord Blood.

Introduction Little is known about the prevalence of conditions potentially amenable to cellular therapy among families storing umbilical cord blood in private cord blood banks. Methods A cross-sectional study of families with at least one child who stored umbilical cord blood in the largest private cord blood bank in the United States was performed. Respondent families completed a questionnaire to determine whether children with stored cord blood or a first-degree relative had one or more of 16 conditions amenable primarily to allogeneic stem cell transplant ("transplant indications") or 16 conditions under investigation for autologous stem cell infusion ("regenerative indications"), regardless of whether they received a transplant or infusion. Results 94,803 families responded, representing 33.3 % of those surveyed. Of respondent families, 16.01 % indicated at least one specified condition. 1.64 % reported at least one first-degree member with a transplant indication potentially treatable with an allogeneic stem cell transplant. The most common transplant indications reported among first-degree family members were Non-Hodgkin's Lymphoma (0.33 %), Hodgkin's Lymphoma (0.30 %), and Acute Lymphoblastic Leukemia (0.28 %). 4.23 % reported at least one child with a regenerative indication potentially treatable with an autologous stem cell infusion. The most common regenerative indications among children with stored umbilical cord blood were Autism/Autism Spectrum Disorder/Apraxia (1.93 %), Other Developmental Delay (1.36 %), and Congenital Heart Defect (0.87 %). Discussion Among families storing umbilical cord blood in private cord blood banks, conditions for which stem cell transplant or infusion may be indicated, or are under investigation, appear to be prevalent, especially for regenerative medicine indications.

Emerging trends and new developments in regenerative medicine: a scientometric update (2000 - 2014).

INTRODUCTION: Our previous scientometric review of regenerative medicine provides a snapshot of the fast-growing field up to the end of 2011. The new review identifies emerging trends and new developments appearing in the literature of regenerative medicine based on relevant articles and reviews published between 2000 and the first month of 2014. AREAS COVERED: Multiple datasets of publications relevant to regenerative medicine are constructed through topic search and citation expansion to ensure adequate coverage of the field. Networks of co-cited references representing the literature of regenerative medicine are constructed and visualized based on a combined dataset of 71,393 articles published between 2000 and 2014. Structural and temporal dynamics are identified in terms of most active topical areas and cited references. New developments are identified in terms of newly emerged clusters and research areas. Disciplinary-level patterns are visualized in dual-map overlays. EXPERT OPINION: While research in induced pluripotent stem cells remains the most prominent area in the field of regenerative medicine, research related to clinical and therapeutic applications in regenerative medicine has experienced a considerable growth. In addition, clinical and therapeutic developments in regenerative medicine have demonstrated profound connections with the induced pluripotent stem cell research and stem cell research in general. A rapid adaptation of graphene-based nanomaterials in regenerative medicine is evident. Both basic research represented by stem cell research and application-oriented research typically found in tissue engineering are now increasingly integrated in the scientometric landscape of regenerative medicine. Tissue engineering is an interdisciplinary field in its own right. Advances in multiple disciplines such as stem cell research and graphene research have strengthened the connections between tissue engineering and regenerative medicine.

Association vs. causality in transfusion medicine: understanding multivariable analysis in prediction vs. etiologic research.

In the current medical literature, etiologic and prediction research aims are frequently confused. Investigators tend to use principles from prediction research for their etiologic research questions, which results in misleading interpretation of risk factor findings at hand. We used a questionnaire-based survey to quantify the proportion of International Society of Blood Transfusion (ISBT) 2012, Cancun, visitors who felt confident with a causal interpretation of a stepwise logistic regression model. We designed and distributed a short online questionnaire survey addressing questions about a constructed abstract entitled "Association of transfusion and clinical outcomes in a large cohort" among the participants of ISBT 2012, Cancun. In addition to asking questions about the demographics (age, sex, country of employment, and highest education level) of the participants, we designed 7 statements representing possible interpretations of the findings presented in the abstract and asked the participants to mark Agree, Disagree, or Do Not Know for each statement. Based on the responses to these statements, we quantified the proportion of participants who inferred causality from stepwise multivariable models built to examine a question of association (or prediction).Thirty percent to 40% of the respondents agreed that a stepwise model was a valid method to adjust for confounding, and 60% of them agreed to a causal interpretation of a model built for prediction purposes. These findings suggest that a large proportion of ISBT visitors confuse etiology with prediction in the published transfusion medicine research. Using the results as a platform, we aim to delineate the distinction between etiologic and prediction research, issues of confounding accompanying these research aims and how a multivariable model deals with confounding.

Blood component recalls and market withdrawals: frequency, reasons, and management in the United States.

In a previous article, we reviewed the management of blood component recalls and withdrawals (G. Ramsey. Transfusion Med Rev 2004;18:36-45). Since then, US rates of recall and biological product deviation for blood components have improved significantly, particularly with regard to reduced recalls for donor infectious disease risks or testing. However, analysis of the current data from the US Food and Drug Administration suggests that 1 (0.4%) in 250 blood components is involved in market withdrawals and quarantines, with 1 in 5800 components formally recalled. Most of these units, unfortunately, had already have been transfused. The U.S. Food and Drug Administration has issued several recent guidances that address transfusion service actions for dealing with specific infectious disease problems. This present article updates our 2004 recommendations as to when to notify physicians about transfused nonconforming blood components.

Global update: USA.

Despite the political nature of stem cell research, this area of science continues to flourish in the USA. In 2011, the NIH funded approximately US$1.2 billion in stem cell research - a steady increase from past years - with US$123 million devoted to human embryonic stem cells. According to the ISI Web of Science, more than 4000 US-authored stem cell publications were produced in 2011, accounting for approximately 38% of the world total. Approximately a quarter of these publications were collaborations with authors from other countries.

Global update: Canada.

If Canadians have a global reputation for being 'nice', then our propensity for scientists to collaborate should come as no surprise. The Canadian stem cell and regenerative medicine field is particularly strong in terms of collaboration, research results and innovative programs to leverage investments in the sector. Canada continues to see significant achievements and changes that will have a broad impact on the ability to move translational research forward in the near future.

Global update: UK.

2012 has been an exciting year in the UK with substantial development on every front - research, clinical, industry and government. In particular, the focus has now moved to encompass far more post-research activities, with the continued enrolment of patients onto two pioneering Phase I clinical trials: ReNeuron's ReN001 stem cell therapy for stroke (PISCES) in Southern General Hospital, Greater Glasgow and Advanced Cell Technology's retinal pigment epithelial cells derived from human embryonic stem cells for Stargardts macular dystrophy and dry age-related macular degeneration at Moorfields Eye Hospital, London. The funding landscape for the sector has evolved from previous years to more fully embrace development and translation, including the provision of £180 million available for biomedical research via the Biomedical Catalyst Fund (joint Technology Strategy Board and Medical Research Council [MRC] funding) and a further £25 million through the UK Research Council's UK Regenerative Medicine Platform initiative, as well as ongoing developments with the Cell Therapy Catapult, which all act to further encourage a pan-UK collaborative environment. Overall, the UK cell therapy community continues to thrive and impact heavily upon the worldwide sector, with an established research base, a solid approach to translation and a small but growing commercial sector that is going from strength to strength.

Global update: Sweden.

Swedish researchers have been very active in the stem cell field for many years. They have pioneered areas such as clinical treatment of Parkinson's disease, developmental biology including early stem cells, human embryonic stem cells, induced pluripotent stem cells and human mesenchymal stem cells. The Swedish Research Council and other funding organizations have been very positive for stem cell research, and there is a favorable law in Sweden regulating human embryonic stem cell research. Many groups have been active partners in projects funded by the European Commission. Clinical trials are ongoing with mesenchymal stem cells in graft versus host disease and osteogenesis imperfecta. Successful transplantations of trachea using a tissue-engineered product with cells cultured into a scaffold have been made recently. Optimizing the stem cell type for these constructs is ongoing.

Global update: Brazil.

Research using human embryonic stem cells (hESCs) was debated for 4 years in the Brazilian Supreme Court before being legally approved in 2008. Before that, only research with adult stem cells was supported by federal funding. Even with the ban on hESC research until 2008 the country made significant advances in stem cell research in the last decade. Right after legislation permitted, the first Brazilian hESC line was derived, still in 2008. Achievements in the field were supported by policies directed to provide federal funding for stem cell research by the Ministry of Health. Investments since 2005 have mounted to over US$50 million, financing 110 projects, ranging from basic to clinical research.