Update on stem cell therapy for cerebral palsy

Introduction: Due to the publicity about stem cell transplantation for the treatment of cerebral palsy, many families seek information on treatment, and many travel overseas for cell transplantation. Even so, there is little scientific confirmation of benefit, and therefore existing knowledge in the field must be summarized.

Areas covered: This paper addresses the clinical protocols examining the problem, types of stem cells available for transplant, experimental models used to test the benefit of the cells, possible mechanisms of action, potential complications of cell treatment and what is needed in the field to help accelerate cell-based therapies.

Expert opinion: While stem cells may be beneficial in acute injuries of the CNS the biology of stem cells is not well enough understood in chronic injuries or disorders such as cerebral palsy. More work is required at the basic level of stem cell biology, in the development of animal models, and finally in well-conceived clinical trials.     

Toward the use of endometrial and menstrual blood mesenchymal stem cells for cell-based therapies

Introduction: Bone marrow is a widely used source of mesenchymal stem cells (MSCs) for cell-based therapies. Recently, endometrium – the highly regenerative lining of the uterus – and menstrual blood have been identified as more accessible sources of MSCs. These uterine MSCs include two related cell types: endometrial MSCs (eMSCs) and endometrial regenerative cells (ERCs).

Areas covered: The properties of eMSCs and ERCs and their application in preclinical in vitro and in vivo studies for pelvic organ prolapse, heart disorders and ischemic conditions are reviewed. Details of the first clinical Phase I and Phase II studies will be provided.

Expert opinion: The authors report that eMSCs and ERCs are a readily available source of adult stem cells. Both eMSCs and ERCs fulfill the key MSC criteria and have been successfully used in preclinical models to treat various diseases. Data on clinical trials are sparse. More research is needed to determine the mechanism of action of eMSCs and ERCs in these regenerative medicine models and to determine the long-term benefits and any adverse effects after their administration.     

Manufacturing and banking of mesenchymal stem cells

Introduction: Mesenchymal stem cells (MSC) and MSC-like cells hold great promise and offer many advantages for developing effective cellular therapeutics. Current trends indicate that the clinical application of MSC will continue to increase markedly. For clinical applications, large numbers of MSC are usually required, ideally in an off-the-shelf format, thus requiring extensive MSC expansion ex vivo and subsequent cryopreservation and banking.

Areas covered: To exploit the full potential of MSC for cell-based therapies requires overcoming significant cell-manufacturing, banking and regulatory challenges. The current review will focus on the identification of optimal cell source for MSC, the techniques for production scale-up, cryopreservation and banking and the regulatory challenges involved.

Expert opinion: There has been considerable success manufacturing and cryopreserving MSC at laboratory scale. Surprisingly little attention, however, has been given to translate these technologies to an industrial scale. The development of cost-effective advanced technologies for producing and cryopreserving commercial-scale MSC is important for successful clinical cell therapy.     

In vivo stem cell tracking in neurodegenerative therapies

Introduction: Cell transplants to replace cells lost due to injury or degenerative diseases, for which there are currently no cures, are being pursued in a wide range of experimental models. Thus, the application of stem cell-based therapies to treat neurodegenerative and traumatic injuries is now a clinical reality. However, the monitoring of cellular grafts, non-invasively, is an important aspect of the ongoing efficacy and safety assessment of cell-based therapies. Hence, there is a need for non-invasive imaging techniques to ensure that transplants are not only administered to the relevant site, but also allow the monitoring of inappropriate cellular migration to improve our understanding of stem cell migration in the context of the whole organism.

Areas covered: This review provides an up to date overview of molecular imaging approaches that have been used for visualizing and tracking transplanted stem cells, in vivo.

Expert opinion: It's important to emphasize that the application of molecular imaging to interrogate transplanted cells may require one or even two imaging modalities to provide a reasonable assessment of transplanted cells in specific organs.     

Perivascular cells as mesenchymal stem cells

Importance of the field: Mesenchymal stem cells are multipotent adult stem cell populations that have broad differentiation plasticity and immunosuppressive potential that render them of great importance in cell-based therapies. They are identified by in vitro characteristics based on their differentiation potential for clinical approaches while their biological properties and in vivo identities are often less understood.

Areas covered in this review: Recent research carried out in the last decade on mesenchymal stem cell biology suggests that mesenchymal stem cells from various tissues reside in a perivascular location and these can be identified as pericytes that function as mural cells in microvessels.

What the reader will gain: This review covers recent progress on understanding the link between pericytes and mesenchymal stem cells discussing specific points such as response to injury and tissue-specific functions.

Take home message: Despite a long and controversial history, there is a growing acceptance that perivascular cells are connected with mesenchymal stem cells, all that is really lacking is genetic evidence to show differentiation of pericytes into different cells types.     

The known-unknowns in spinal cord injury,with emphasis on cell-based therapies – a review with suggestive arenas for research

Introduction: In spite of extensive research, the progress toward a cure in spinal cord injury (SCI) is still elusive, which holds good for the cell- and stem cell-based therapies. We have critically analyzed seven known gray areas in SCI, indicating the specific arenas for research to improvise the outcome of cell-based therapies in SCI.

Areas covered: The seven, specific known gray areas in SCI analyzed are: i) the gap between animal models and human victims; ii) uncertainty about the time, route and dosage of cells applied; iii) source of the most efficacious cells for therapy; iv) inability to address the vascular compromise during SCI; v) lack of non-invasive methodologies to track the transplanted cells; vi) need for scaffolds to retain the cells at the site of injury; and vii) physical and chemical stimuli that might be required for synapses formation yielding functional neurons.

Expert opinion: Further research on scaffolds for retaining the transplanted cells at the lesion, chemical and physical stimuli that may help neurons become functional, a meta-analysis of timing of the cell therapy, mode of application and larger clinical studies are essential to improve the outcome.     

The potential of cell-based therapy in lung diseases

Introduction: Many lung diseases have high morbidity and mortality rates and there are no cures or treatments apart from mechanical ventilation or transplantation. Cell-based therapies are currently an area of intense research, and many groups are working to translate successful in vitro results into treatments that are safe for patients.

Areas covered: This review discusses several types of stem and progenitor cells that have been proven likely candidates for cell therapies, as well as their applications so far in specific acute and chronic lung diseases, focusing on their mechanisms of action and how best they can be directed toward clinical aims.

Expert opinion: The research on cell therapies for the lung, particularly regarding mesenchymal stem cells (MSCs), is promising, but there is still much uncertainty surrounding the mechanisms of MSC action and the factors relevant to clinical applications such as the optimal timing of dosage. Future studies will focus on the microenvironment of the stem cells, including the role of microRNAs and extracellular vesicles.     

Prolyl hydroxylase inhibitors act as agents to enhance the efficiency of cell therapy

Introduction: In stem cell-based therapy as a subtype of regenerative medicine, stem cells can be used to replace or repair injured tissue and cells in order to treat disease. Stem cells have the ability to integrate into injured areas and produce new cells via processes of proliferation and differentiation. Several studies have demonstrated that hypoxia increases self-renewal, proliferation and post-homing differentiation of stem cells through the regulation of hypoxia-inducible factor-1 (HIF-1)-mediated gene expression. Thus, pharmacological interventions including prolyl hydroxylase (PHD) inhibitors are considered as promising solutions for stem cell-based therapy. PHD inhibitors stabilize the HIF-1 and activate its pathway through preventing proteasomal degradation of HIF-1.

Areas covered: This review focuses on the role of hypoxia, HIF-1 and especially PHD inhibitors on cell therapy. PHD structure and function are discussed as well as their inhibitors. In addition, we have investigated several preclinical studies in which PHD inhibitors improved the efficiency of cell-based therapies.

Expert opinion: The data reviewed here suggest that PHD inhibitors are effective operators in improving stem cell therapy. However, because of some limitations, these compounds should be properly examined before clinical application.     

Stem cells and stroke: opportunities,challenges and strategies

Introduction: Stroke remains the leading cause of disability in the Western world. Despite decades of work, no clinically effective therapies exist to facilitate recovery from stroke. Stem cells may have the potential to minimize injury and promote recovery after stroke.

Areas covered: Transplanted stem cells have been shown in animal models to migrate to the injured region, secrete neurotrophic compounds, promote revascularization, enhance plasticity and regulate the inflammatory response, thereby minimizing injury. Endogenous neural stem cells also have a remarkable propensity to respond to injury. Under select conditions, subventricular zone progenitors may be mobilized to replace lost neurons. In response to focal infarcts, neuroblasts play important trophic roles to minimize neural injury. Importantly, these endogenous repair mechanisms may be experimentally augmented, leading to robust improvements in function. Ongoing clinical studies are now assessing the safety and feasibility of cell-based therapies for stroke.

Expert opinion: We outline the unique challenges and potential pitfalls in the clinical translation of stem cell research for stroke. We then detail what we believe to be the specific basic science and clinical strategies needed to overcome these challenges, fill remaining gaps in knowledge and facilitate development of clinically viable stem cell-based therapies for stroke.     

Human umbilical cord mesenchymal stem cells: an overview of their potential in cell-based therapy

Introduction: Human umbilical cord mesenchymal stem cells (HUC-MSCs) are one of the typical adult stem cells; they have superiorities including low immunogenicity, non-invasive harvest procedure, easy expansion in vitro, and ethical access compared with stem cells from other sources. Therefore, HUC-MSCs are a promising candidate for cell-based therapy.

Areas covered: Here we reviewed the development of stem cell-based therapy, the manufacturing and banking process of HUC-MSCs, the emerging clinical studies in the field of cancer, central nervous system diseases, liver diseases and graft-versus-host disease, the potential therapeutic mechanisms, as well as challenges of HUC-MSCs in clinical translation.

Expert opinion: HUC-MSCs seem to be an optimal choice for stem cell-based therapy. However, before the cells translate from basic to clinical research, some problems still remain to be solved: i) building regulatory guidelines as well as an efficient and safe manufacturing procedure; ii) establishing donor’s genetic testing and long-term closely monitoring system; iii) conducting further clinical trials to determine the optimum and standard dosage, time, route, frequency and many other technical issues of HUC-MSCs transplantation.     

Co-cultivation of progenitor cells enhanced osteogenic gene expression and angiogenesis potential in vitro

ObjectivesThe efficiencies of osteogenesis and angiogenesis present challenges that need to be overcome before bone tissue engineering can be widely applied to clinical uses. We aimed to optimize an in vitro culture system to enhance osteogenesis and angiogenesis. We investigated if hematopoietic stem cells (HSCs) promoted osteogenesis in vitro when co-cultured with mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs).MethodsMSC/HSC, MSC/EPC/HSC, and MSC/EPC co-cultures were incubated for 21 days. Alkaline phosphatase (ALP) activity and calcium content were analyzed to assess mineralization. Expression levels of genes encoding osteogenesis-related proteins (ALP (ALPL), collagen type IA (COL1A1), osteocalcin (BGLAP), and osteopontin (OSTP)) were also evaluated by measuring mRNA levels at day 28. Angiogenesis was evaluated by tube-formation assay.ResultsCOL1A1, OSTP, ALPL, and BGLAP genes were upregulated in MSC/HSC and MSC/EPC/HSC co-cultures compared with the MSC/EPC group. Upregulation was strongest in the MSC/EPC/HSC co-cultures. There were no significant changes in ALP levels and calcium content, but ALP activity was slightly higher and calcium content was relatively lower in the MSC/EPC and MSC/EPC/HSC groups.ConclusionsCo-culture of MSCs with HSCs or EPCs/HSCs upregulated the expression of osteogenesis-related genes but did not affect the efficiency of osteogenesis.     

Harnessing mesenchymal stem cell homing as an anticancer therapy

ABSTRACT

Introduction: Mesenchymal stromal cells (MSCs) are non-hematopoietic progenitor cells that have been exploited as vehicles for cell-based cancer therapy. The general approach is based on the innate potential of adoptively applied MSC to undergo facilitated recruitment to malignant tissue. MSC from different tissue sources have been engineered using a variety of therapy genes that have shown efficacy in solid tumor models.

Areas covered: In this review we will focus on the current developments of MSC-based gene therapy, in particular the diverse approaches that have been used for MSCs-targeted tumor therapy. We also discuss some outstanding issues and general prospects for their clinical application.

Expert opinion: The use of modified mesenchymal stem cells as therapy vehicles for the treatment of solid tumors has progressed to the first generation of clinical trials, but the general field is still in its infancy. There are many questions that need to be addressed if this very complex therapy approach is widely applied in clinical settings. More must be understood about the mechanisms underlying tumor tropism and we need to identify the optimal source of the cells used. Outstanding issues also include the therapy transgenes used, and which tumor types represent viable targets for this therapy.     

Potential benefits of allogeneic bone marrow mesenchymal stem cells for wound healing

Introduction: It is becoming increasingly evident that select adult stem cells have the capacity to participate in repair and regeneration of damaged and/or diseased tissues. Mesenchymal stem cells have been among the most studied adult stem cells for the treatment of a variety of conditions, including wound healing.

Areas covered: Mesenchymal stem cell features potentially beneficial to cutaneous wound healing applications are reviewed.

Expert opinion: Given their potential for in vitro expansion and immune modulatory effects, both autologous and allogeneic mesenchymal stem cells appear to be well suited as wound healing therapies. Allogeneic mesenchymal stem cells derived from young healthy donors could have particular advantage over autologous sources where age and systemic disease can be significant factors.     

Epigenetic approaches to regeneration of bone and cartilage from stem cells

Introduction: Embryonic stem cells (ESCs) or adult stem cells, especially mesenchymal stem cells (MSCs), have been intensively studied for skeletal tissue regeneration including bone and cartilage. Epigenetic mechanisms play essential roles in stem cell maintenance and differentiation. However, little is known about the epigenetic regulation of osteogenesis and chondrogenesis of stem cells.

Areas covered: In this review, features of ESCs and adult stem cells, epigenetics and chromatin structure, as well as epigenetic mechanisms, such as chromatin remodeling, DNA methylation and histone modifications, polycomb group (PcG) proteins and microRNAs are described. Epigenetic researches of stem cell are introduced.

Expert opinion: Epigenetic alterations of stem cell during the in vitro differentiation can be controlled for clinical applications. MSCs are effective resources for skeletal tissue regeneration in both undifferentiated and differentiated states. Understanding epigenetic signatures of MSC is crucial to maintain the stemness. In addition, investigation of epigenetic changes in the differentiation of MSCs is very important to develop methods or chemicals to promote efficient differentiation of MSCs. Inhibition of PcG protein enhancer of zeste (Ezh2) a chromatin modifier, could be a promising candidate to improve MSC differentiation by decreasing Ezh2-mediated H3K27me3.     

Stem cells for tendon tissue engineering and regeneration

Importance of the field: Tendon injuries are common especially in sports activities, but tendon is a unique connective tissue with poor self-repair capability. With advances in stem cell biology, tissue engineering is becoming increasingly powerful for tissue regeneration. Stem cells with capacity of multipotency and self-renewal are an ideal cell source for tissue engineering.

Areas covered in this review: This review focus on discussing the potential strategies including inductive growth factors, bio-scaffolds, mechanical stimulation, genetic modification and co-culture techniques to direct tendon-lineage differentiation of stem cells for complete tendon regeneration. Attempting to use embryonic stem cells as seed cells for tendon tissue engineering have achieved encouraging results. The combination of chemical and physical signals in stem cell microenvironment could be regulated to induce differentiation of the embryonic stem cells into tendon.

What the reader will gain: We summarize fundamental questions, as well as future directions in tendon biology and tissue engineering.

Take home message: Multifaceted technologies are increasingly required to control stem cell differentiation, to develop novel stem cell-based therapy, and, ultimately, to achieve more effective repair or regeneration of injured tendons.     

Advances in stem cell therapy for amyotrophic lateral sclerosis

Introduction: Amyotrophic Lateral Sclerosis (ALS) is a progressive, incurable neurodegenerative disease that targets motoneurons. Cell-based therapies have generated widespread interest as a potential therapeutic approach but no conclusive results have yet been reported either from pre-clinical or clinical studies.

Areas covered: This is an integrated review of pre-clinical and clinical studies focused on the development of cell-based therapies for ALS. We analyze the biology of stem cell treatments and results obtained from pre-clinical models of ALS and examine the methods and the results obtained to date from clinical trials. We discuss scientific, clinical, and ethical issues and propose some directions for future studies.

Expert opinion: While data from individual studies are encouraging, stem-cell-based therapies do not yet represent a satisfactory, reliable clinical option. The field will critically benefit from the introduction of well-designed, randomized and reproducible, powered clinical trials. Comparative studies addressing key issues such as the nature, properties, and number of donor cells, the delivery mode and the selection of proper patient populations that may benefit the most from cell-based therapies are now of the essence. Multidisciplinary networks of experts should be established to empower effective translation of research into the clinic.     

Repairing the corneal epithelium using limbal stem cells or alternative cell-based therapies

Introduction: The corneal epithelium is maintained by limbal stem cells (LSCs) that reside in the basal epithelial layer of the tissue surrounding the cornea termed the limbus. Loss of LSCs results in limbal stem cell deficiency (LSCD) that can cause severe visual impairment. Patients with partial LSCD may respond to conservative therapies designed to rehabilitate the remaining LSCs. However, if these conservative approaches fail or, if complete loss of LSCs occurs, transplantation of LSCs or their alternatives is the only option. While a number of clinical studies utilizing diverse surgical and cell culture techniques have shown favorable results, a universal cure for LSCD is still not available. Knowledge of the potential risks and benefits of current approaches, and development of new technologies, is essential for further improvement of LSCD therapies.

Areas covered: This review focuses on cell-based LSCD treatment approaches ranging from current available clinical therapies to preclinical studies of novel promising applications.

Expert opinion: Improved understanding of LSC identity and development of LSC expansion methods will influence the evolution of successful LSCD therapies. Ultimately, future controlled clinical studies enabling direct comparison of the diverse employed approaches will help to identify the most effective treatment strategies.     

The ‘sweet’ spot of cellular pluripotency: protein glycosylation in human pluripotent stem cells and its applications in regenerative medicine

Introduction: Human pluripotent stem cells (hPSCs) promise for the future of regenerative medicine. The structural and biochemical diversity associated with glycans makes them a unique type of macromolecule modification that is involved in the regulation of a vast array of biochemical events and cellular activities including pluripotency in hPSCs. The primary focus of this review article is to highlight recent advances in stem cell research from a glycobiological perspective. We also discuss how our understanding of glycans and glycosylation may help overcome barriers hindering the clinical application of hPSC-derived cells.

Areas covered: A literature survey using NCBI-PubMed and Google Scholar was performed in 2014.

Expert opinion: Regenerative medicine hopes to provide novel strategies to combat human disease and tissue injury that currently lack effective therapies. Although progress in this field is accelerating, many critical issues remain to be addressed in order for cell-based therapy to become a practical and safe treatment option. Emerging evidence suggests that protein glycosylation may significantly influence the regulation of cellular pluripotency, and that the exploitation of protein glycosylation in hPSCs and their differentiated derivatives may lead to transformative and translational discoveries for regenerative medicine. In addition, hPSCs represent a novel research platform for investigating glycosylation-related disease.     

Cx601 (darvadstrocel) for the treatment of perianal fistulizing Crohn’s disease

Introduction: Given the well-documented difficulty to treat perianal fistulizing Crohn’s disease (pCD), with 40% of patients experiencing recurrence even after reiterative surgery and advanced medical therapy, research in this field has focused on the role of mesenchymal stem cells (MSC).

Areas covered: The aim of this article is to furnish an overview of the pathogenetic mechanisms, clinical applications and evidences for the use of MSC for pCD with particular focus on adipose-derived allogenic MSC including darvadstrocel.

Expert Opinion: The effect of MSC on fistula healing is probably mediated by their anti-inflammatory properties more than by their ability to engraft and trans-differentiate in the healthy tissue. A holistic treatment of pCD, addressing different pathophysiological factors, may represent the key for an improvement in the healing rate. In this setting, MSC might play a role as ‘augmentation’ therapy in combination with more conventional treatments. Whether MSC have benefit in non-complex fistula in biological naïve patients, in complex fistula with many tracts and/or in rectovaginal fistulas, are unexplored fields that need further investigation. A central registry of pCD patients undergoing treatment with MSC should be created in order to elucidate the efficacy, safety and costs of stem cells treatment on long term follow up.