Translational Stem Cell Research Research Articles

Cell-Based Therapies for the Treatment of Traumatic Brain Injury: Promises and Trajectories

Traumatic Brain Injury (TBI) is a debilitating condition that poses a significant public health concern. Historically linked to motor vehicle accidents, the epidemiology of TBI has evolved. Falls now emerge as the predominant cause, particularly among older adults. Sport-related TBIs have also garnered increased attention due to concerns regarding long-term neurological sequelae. To date, therapeutic interventions remain limited and have yet to yield substantial clinical benefits. Cell-based therapies offer promising avenues for neural repair and regeneration: endogenous stem cell therapies capitalize on endogenous pools that can be triggered by the injury and further enhanced by therapeutic approaches. In contrast, exogenous cell therapies provide an exogenous source of cells. However, challenges such as age-related decline in neurogenesis, age-related inflammation, and the heterogeneity of TBI present significant hurdles to overcome. Moreover, translating stem cell research from the laboratory to clinical applications necessitates the adherence to good manufacturing practice standards, which presents distinct obstacles. Addressing these challenges requires a multifaceted approach, including careful patient selection in clinical trials, appropriate experimental models, and the optimization of therapeutic techniques. Ultimately, a combination of strategies is likely to yield the most promising outcomes in the pursuit of effective TBI therapies.

Clinical translation of pluripotent stem cell-based therapies: successes and challenges.

The translational stem cell research field has progressed immensely in the past decade. Development and refinement of differentiation protocols now allows the generation of a range of cell types, such as pancreatic β-cells and dopaminergic neurons, from human pluripotent stem cells (hPSCs) in an efficient and good manufacturing practice-compliant fashion. This has led to the initiation of several clinical trials using hPSC-derived cells to replace lost or dysfunctional cells, demonstrating evidence of both safety and efficacy. Here, we highlight successes from some of the hPSC-based trials reporting early signs of efficacy and discuss common challenges in clinical translation of cell therapies.

Re-defining and tackling the emerging challenges in stem cell research and translation: A report of the 10th CSSCR annual meeting.

The 10th congress of the Chinese Society for Stem Cell Research was held from 11 to 13 October 2020 at Guiyang International Eco‐Conference Center in Guizhou (Southwest China) with 700 offline participants (and 500 online participants). With a theme adopted from a poem by Mao Zedong during the long march, ‘However difficult it might appear; the challenges will be overcome’, the congress provided opportunities for the fast‐growing field to exchange ideas among people from academia, industry and regulatory authorities, to help accelerate translation. Eight plenary lectures and six concurrent sessions on cell fate decision, stem cell metabolism, neural stem cells and neural regeneration, organoids and disease models, tissue and organ regeneration and clinical translation of stem cell research were covered, including 77 oral presentations and 75 poster presentations. The congress also included special programmes of a youth forum, a lecture award programme, a flagship journal forum and a dedicated networking session. This 3‐day event will significantly boost the stem cell research in an era closing to application.

Translating stem cell research into development of cellular drugs-a perspective from manufacture of stem cell products and CMC considerations.

The development of human pluripotent stem cell (PSC)‐derived medicinal products has been gathering steam in recent years, but the translation of research protocols into GMP production remains a daunting task. The challenges not only reside with the nature of cellular therapeutics but are also rooted in the general inexperience in industry‐scale production of stem cell products. Manufacturers of PSC‐derived products should be aware of the technical nuances and take a holistic approach toward early planning and engagement with their academic partners. While not all issues will be readily resolved soon, the collective knowledge and consensus by the manufacturers and key stakeholders will help to guide rapid progression of the field.

Validation of baboon pluripotent cells as a model for translational stem cell research

Translation of stem cell therapies to the clinic will be most successful following optimization of efficacy and safety in appropriate preclinical model systems. Among available models, nonhuman primates (NHPs) provide the most accurate recapitulation of human anatomy, physiology, genetics and epigenetics. Here, we show that baboon pluripotent cells (PSCs) recapitulate key molecular features of human PSCs with greater accuracy than that found in PSCs from non-primate species such as mice. Specifically, baboon and human PSCs exhibit greater conservation of gene expression patterns, higher sequence and structural homology among pluripotency factors, more equivalent genome-wide patterns of histone and DNA methylation modifications, and similar maintenance of bivalent programming of developmental genes than that found between human and non-primate PSCs.

International stem cell tourism: a critical literature review and evidence-based recommendations.

Stem cell tourism is an emerging area of medical tourism activity. Frustrated by the slow translation of stem cell research into clinical practice, patients with debilitating conditions often seek therapeutic options that are not appropriately regulated. This review summarises recent developments in the field of stem cell tourism and provides clinicians with the information necessary to provide basic pretravel health advice to stem cell tourists. PubMed and Scopus databases were consulted for relevant publications, using combinations of the terms ‘stem cell’, ‘tourism’, ‘regenerative medicine’, ‘international’, ‘travel medicine’ and ‘environmental health’. The leading countries in the international stem cell tourism market are the USA, China, India, Thailand and Mexico. As the majority of clinics offering stem cell therapies are based in low- and-middle-income countries, stem cell tourists place themselves at risk of receiving an unproven treatment, coupled with the risk of travel-related illnesses. These clinics do not generally provide even basic travel health information on their websites. In addition to often being ineffective, stem cell therapies are associated with complications such as infection, rejection and tumorigenesis. Physicians, researchers, regulatory bodies, advocacy groups and medical educators are encouraged to work together to improve patient and physician education and address current legislative deficiencies.

Development of Disease Specific Stem Cell-Lines for Therapeutic Applications: Advantages and Progress in Translational Stem Cell Research

One of the most significant developments in cell and developmental biology in recent years has been the incredible interest in the potential of stem cells in regenerative medicine. ln spite of the ongoing political, ethical and scientific challenges interest in the potential clinical utility of stem continues to increase. Extraordinary developments in the field of stem cell research continued in developing disease-specific stem cell lines; advances were made in creating induced pluripotent stem (iPS) cell lines using technologies compatible with clinical use; and the US Food and Drug Administration (FDA) gave approval for the first clinical trial using cells derived from human embryonic stem cells (hESC) for the treatment of spinal cord injury. Both regenerative medicine and tissue engineering rely on the success of stem cell technology. Advances in the embryonic and adult stem cell research, particularly over the past two decades, have enabled cell-based therapies. Now it is also possible to genetically reprogram the somatic cells and induce pluripotency in them to function in a manner similar to embryonic stem cells. However, further studies on teratogenic or tumorigenic properties, cellular dose, cell proliferation, senescence, karyotyping, and immunosuppressive activity are essential to translate the technology into clinical application.

Renal Regeneration: Stem Cell-Based Therapies to Battle Kidney Disease

While the worldwide prevalence of kidney disease is increasing rapidly, the current therapeutic repertoire for these patients is often limited to dialysis and organ transplantation. However, advances in developmental and stem cell biology have highlighted the potential of stem cells for the development of novel renal regeneration therapies. While there are currently no approved stem cell-based treatments for kidney disease, various types of stem cells have been shown to facilitate regeneration of kidney tissue in preclinical models of both acute and chronic kidney injury. This review summarises the current status of stem cell-based therapies to battle kidney disease. In addition, future directions for the clinical translation of stem cell research towards development of novel renal regeneration therapies are discussed.

Cellular Internalization-Induced Aggregation of Porous Silicon Nanoparticles for Ultrasound Imaging and Protein-Mediated Protection of Stem Cells.

Nanotechnology employs multifunctional engineered materials in the nanoscale range that provides many opportunities for translational stem cell research and therapy. Here, a cell-penetrating peptide (virus-1 transactivator of transcription)-conjugated, porous silicon nanoparticle (TPSi NP) loaded with the Wnt3a protein to increase both the cell survival rate and the delivery precision of stem cell transplantation via a combinational theranostic strategy is presented. The TPSi NP with a pore size of 10.7 nm and inorganic framework enables high-efficiency loading of Wnt3a, prolongs Wnt3a release, and increases antioxidative stress activity in the labeled mesenchymal stem cells (MSCs), which are highly beneficial properties for cell protection in stem cell therapy for myocardial infarction. It is confirmed that the intracellular aggregation of TPSi NPs can highly amplify the acoustic scattering of the labeled MSCs, resulting in a 2.3-fold increase in the ultrasound (US) signal compared with that of unlabeled MSCs. The translational potential of the designed nanoagent for real-time US imaging-guided stem cell transplantation is confirmed via intramyocardial injection of labeled MSCs in a nude mouse model. It is proposed that the intracellular aggregation of protein drug-loaded TPSi NPs could be a simple but robust strategy for improving the therapeutic effect of stem cell therapy.

Perspectives on the New ISSCR Guidelines for Stem Cell Research and Clinical Translation

This review seeks to highlight key elements of the ISSCR 2016 Guidelines for Stem Cell Research and Clinical Translation, describe apparent influences on the Guidelines, provide an analysis of the utility and the potential impact of the Guidelines on the field of stem cell research, and propose considerations for the future versions of the Guidelines. Part ethical code of conduct, part “how-to” instructions, and part policy declaration, this version of the Guidelines forms ISSCR’s most up-to-date recommendations and guidance on the topic of stem cell clinical translation. In the revised set of Guidelines, ISSCR has asserted the imperative of maintaining the highest ethical standards for clinical translation of stem cell research. The Guidelines set a sound foundation for self-regulation, not only communicating the Society’s position on what is legitimate stem cell research/treatment and what is not, but also fulfilling ISSCR’s mission of providing professional (and public) education regarding the specific steps that should be taken to translate basic research findings to the clinic. Future versions would benefit from more extensive references, including hyperlinks to regulatory authority guidance documents; and improved clarity of the writing style, including avoidance of vague descriptions and the addition of flow charts and/or tables.

Responsible Translation of Stem Cell Research: An Assessment of Clinical Trial Registration and Publications.

SummaryWe assessed the extent to which the publication of clinical trial results of innovative cell-based interventions reflects International Society for Stem Cell Research best practice guidelines. We assessed: (1) characteristics and time to publication of completed trials; (2) quality of reported trials; and (3) results of published trials. We identified and analyzed publications from 1,052 novel stem cell clinical trials: 179 (45.4%) of 393 completed trials had published results; 48 trials were registered by known stem cell tourism clinics, none of which reported results. Completed non-industry-sponsored trials initially published more rapidly, but differences with industry-sponsored trials decreased over time. Most publications reported safety, and 67.3% (mainly early-stage trials) reported positive outcomes. A higher proportion of industry trials reported positive efficacy. Heightened patient expectations for stem cell therapies give rise to ethical obligations for the transparent conduct of clinical trials. Reporting guidelines need to be developed that are specific to early-phase clinical trials.

Concise Review: Increasing the Validity of Cerebrovascular Disease Models and Experimental Methods for Translational Stem Cell Research.

Interspecies differences, anatomical and physiological aspects, as wells as simplified study designs contribute to an overestimation of treatment effects and limit the transferability of experimental results into clinical applications. Confounders of cell therapies for cerebrovascular disorders (CVD) include common CVD comorbidities, frequent medications potentially affecting endogenous and transplanted stem cells, as well as age- and immune-system-related effects. All those can contribute to a substantial modeling bias, ultimately limiting the prospective quality of preclinical research programs regarding the clinical value of a particular cell therapy. In this review, we discuss the nature and impact of most relevant confounders. We provide suggestions on how they can be considered to enhance the validity of CVD models in stem cell research. Acknowledging substantial and sometimes surprising effects of housing conditions, chronobiology, and intersex differences will further augment the translational value of animal models. We finally discuss options for the implementation of high-quality functional and imaging readout protocols. Altogether, this might help to gain a more holistic picture about the therapeutic impact of a particular cell therapy for CVD, but also on potential side and off-site effects of the intervention. Stem Cells 2017;35:1141-1153.

Translational Stem Cell Research–A Marriage of Hope and Hype

The conventional medicine has failed to treat such disorders which arise by cell dysfunction or death, thus necessitating reimbursement of body’s natural regenerative power. Among all the cell types known to date, stem cells provide the best source for augmenting these dysfunctional or dead tissues owing to their intrinsic capability to differentiate into any cell type. Combined with the knowledge of genomics and DNA sequencing, translational stem cell research became not only a reality but it bought a renaissance in regenerative medicine. Like any pioneering technology, this stem cell technology also faced legal, ethical and socio-religious concerns owing to its diverse applications. Human greed and opportunism also crept in which created unnecessary chaos and hype in the sublime and honoured hope which this branch of science had bought into current medicine.

CIRM and UKRMP: Different Ways to Invest in Regenerative Medicine

The California Institute for Regenerative Medicine (CIRM) and the UK Regenerative Medicine Platform (UKRMP) have similar objectives, but their histories, funding mechanisms, and governance could hardly be more different. Here, we compare the two programs and explore their impact in translating stem cell research into clinical applications.

Impact of Feeding Strategies on the Scalable Expansion of Human Pluripotent Stem Cells in Single-Use Stirred Tank Bioreactors.

Human pluripotent stem cells (hPSCs) are a unique source for the, in principle, unlimited production of functional human cell types in vitro, which are of high value for therapeutic and industrial applications. This study applied single-use, clinically compliant bioreactor technology to develop advanced, matrix-free, and more efficient culture conditions for the mass production of hPSCs in scalable suspension culture. Using extensive analytical tools to compare established conditions with this novel culture strategy, unexpected physiological features of hPSCs were discovered. These data allow a more rational process development, providing significant progress in the field of translational stem cell research and medicine.

New ISSCR guidelines: clinical translation of stem cell research.

New ISSCR guidelines: clinical translation of stem cell research.

Concise Review: Primary Cilia: Control Centers for Stem Cell Lineage Specification and Potential Targets for Cell-Based Therapies.

Directing stem cell lineage commitment prevails as the holy grail of translational stem cell research, particularly to those interested in the application of mesenchymal stem cells and adipose-derived stem cells in tissue engineering. However, elucidating the mechanisms underlying their phenotypic specification persists as an active area of research. In recent studies, the primary cilium structure has been intimately associated with defining cell phenotype, maintaining stemness, as well as functioning in a chemo, electro, and mechanosensory capacity in progenitor and committed cell types. Many hypothesize that the primary cilium may indeed be another important player in defining and controlling cell phenotype, concomitant with lineage-dictated cytoskeletal dynamics. Many of the studies on the primary cilium have emerged from disparate areas of biological research, and crosstalk amongst these areas of research is just beginning. To date, there has not been a thorough review of how primary cilia fit into the current paradigm of stem cell differentiation and this review aims to summarize the current cilia work in this context. The goal of this review is to highlight the cilium's function and integrate this knowledge into the working knowledge of stem cell biologists and tissue engineers developing regenerative medicine technologies. Stem Cells 2016;34:1445-1454.

Comparing national home-keeping and the regulation of translational stem cell applications: An international perspective

A very large grey area exists between translational stem cell research and applications that comply with the ideals of randomised control trials and good laboratory and clinical practice and what is often referred to as snake-oil trade. We identify a discrepancy between international research and ethics regulation and the ways in which regulatory instruments in the stem cell field are developed in practice. We examine this discrepancy using the notion of ‘national home-keeping’, referring to the way governments articulate international standards and regulation with conflicting demands on local players at home.Identifying particular dimensions of regulatory tools – authority, permissions, space and acceleration – as crucial to national home-keeping in Asia, Europe and the USA, we show how local regulation works to enable development of the field, notwithstanding international (i.e. principally ‘western’) regulation. Triangulating regulation with empirical data and archival research between 2012 and 2015 has helped us to shed light on how countries and organisations adapt and resist internationally dominant regulation through the manipulation of regulatory tools (contingent upon country size, the state's ability to accumulate resources, healthcare demands, established traditions of scientific governance, and economic and scientific ambitions).

Social Responsibility in Stem Cell Research - Is the News All Bad?

Transparent public discourse about translational stem cell research promotes informed hope about scientific progress and the sustainable development of biotechnologies. Using an a priori coding scheme, we surveyed articles from leading news media about stem cell interventions for neurodegenerative diseases (1991-2014) from United States (n =83), Canada (n = 29), and United Kingdom (n = 65). While, this analysis of translational contexts in the news demonstrates a lingering tendency to celebrate the benefits of research with little context of its caveats even for chronic neurologic diseases, in a departure from many previous studies, the data also reveal conscientious reporting about stem cell tourism and timeframe estimates for the development of relevant therapeutics.

CXCR4: A Potential Chemokine Receptor for Future Regenerative Therapeutic Target

Understanding the molecular mechanisms in regeneration could help the stem cell therapists to improve the clinical practices and could be considered a major milestone in the translation of stem cell research to clinics. Chemokines have been described as one of the most significant singling networks in stem cells homing and regeneration of damaged organs. CXCR4/CXCL12 has been known as a key player in this regard. Expression of CXCR4 has been observed in a number of cells such as mesenchymal stem cells, epithelial cells etc and plays crucial and unique role in the migration of cells towards a cytokine gradient and regulating stem cells trafficking as well as tissue/organ regeneration and embryogenesis.