Stem Cell Therapy For Stroke Research Articles

An Update on Translating Stem Cell Therapy for Stroke from Bench to Bedside.

With a constellation of stem cell sources available, researchers hope to utilize their potential for cellular repair as a therapeutic target for disease. However, many lab-to-clinic translational considerations must be given in determining their efficacy, variables such as the host response, effects on native tissue, and potential for generating tumors. This review will discuss the current knowledge of stem cell research in neurological disease, mainly stroke, with a focus on the benefits, limitations, and clinical potential.

Melatonin-Based Therapeutics for Neuroprotection in Stroke

The present review paper supports the approach to deliver melatonin and to target melatonin receptors for neuroprotection in stroke. We discuss laboratory evidence demonstrating neuroprotective effects of exogenous melatonin treatment and transplantation of melatonin-secreting cells in stroke. In addition, we describe a novel mechanism of action underlying the therapeutic benefits of stem cell therapy in stroke, implicating the role of melatonin receptors. As we envision the clinical entry of melatonin-based therapeutics, we discuss translational experiments that warrant consideration to reveal an optimal melatonin treatment strategy that is safe and effective for human application.

Stem Cell Therapy for Ischaemic Stroke: Translation from Preclinical Studies to Clinical Treatment

No pharmacological intervention has been shown convincingly to improve neurological outcome in stroke patients after the brain tissue is infarcted. While conventional therapeutic strategies focus on preventing brain damage, stem cell treatment has the potential to repair the injured brain tissue. Stem cells not only produce a source of trophic molecules to minimize brain damage caused by ischaemia/reperfusion and promote recovery, but also potentially turn to new cells to replace those lost in ischaemic core. Although preclinical studies have shown promise, stem cell therapy for stroke treatment in human is still at an early stage and it is difficult to draw conclusions from current clinical trials about the efficacy of the different treatments used in humans. This article reviews the potential of various types of stem cells, from embryonic to adult to induced pluripotent stem cells, in stroke therapy, highlights new evidence from the ongoing clinical trials and discusses some of the problems associated with translating stem cell technology to a clinical therapy for stroke.

Perspectives on Assessment of Stem Cell Therapy in Stroke by 18F-FDG PET

As many readers are aware, the work by Dr. Shinya Yamanaka concerning induced pluripotent stem cells (iPSCs) received the Nobel Prize in Physiology or Medicine in 2012. Dr. Yamanaka demonstrated that when 4 genes were transferred to skin cells, they could be reprogrammed into iPSCs, which can then

In Vivo Animal Stroke Models

On average, every four minutes an individual dies from a stroke, accounting for 1 out of every 18 deaths in the United States. Approximately 795,000 Americans have a new or recurrent stroke each year, with just over 600,000 of these being first attack [1]. There have been multiple animal models of stroke demonstrating that novel therapeutics can help improve the clinical outcome. However, these results have failed to show the same outcomes when tested in human clinical trials. This review will discuss the current in vivo animal models of stroke, advantages and limitations, and the rationale for employing these animal models to satisfy translational gating items for examination of neuroprotective, as well as neurorestorative strategies in stroke patients. An emphasis in the present discussion of therapeutics development is given to stem cell therapy for stroke.

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.

Stem Cells in Stroke Treatment: The Promise and the Challenges

Stroke, for some years now the neglected major indication in the pharmaceutical development cupboard, has recently become one of the hot areas for stem cell therapy development. This is driven by better understanding of potential therapeutic opportunities both in the acute and chronic phases and the launch of a series of new early phase clinical trials in a number of countries, driven by positive data in relevant animal models. In addition, the impetus for stem cell product development is motivated by patient demand, with thousands of victims seeking unproven treatments abroad. This article looks at the many challenges facing the development of a stem cell therapy for stroke. These range from product characterization and banking, through nonclinical safety and efficacy to the regulatory requirements for starting patient trials and beyond to maximizing value from carefully designed efficacy trials.

The potential of stem cell therapy for stroke: is PISCES the sign?

Substantial developments in the field of stem cell research point toward novel therapies for the treatment of diseases such as stroke. This review covers the establishment of tissue damage in stroke and the status of current therapies. We evaluate stem cell therapy with respect to other treatments, including clinical, preclinical, and failed, and provide a comprehensive account of stem cell clinical trials for stroke therapy currently underway. Finally, we describe mechanisms through which stem cells improve outcome in experimental stroke as well as potential pitfalls this basic research has identified.

From Bone to Brain: Human Skeletal Stem Cell Therapy for Stroke

Human adult skeletal stem cells, a.k.a. mesenchymal stem cells or marrow stromal cells (MSCs), have been identified as precursors of several different mesenchymal cellular lineages, including osteoblasts, chondrocytes, myoblasts, adipocytes, and fibroblasts, as well as non-mesenchymal lineages including neurons and glial cells. Adult stem cell transplantation is a promising strategy for the treatment of stroke. MSCs are also used as a platform for gene therapies and therapeutic agents. In this review, we discuss recent progress of human skeletal stem cell biology, in vitro differentiation of MSCs into neural stem cells and neurons, MSC therapy for stroke, MSC aging and the challenge of autologous cell therapy for stroke in elderly patients.

Stem cell therapy in stroke: Designing clinical trials

Stroke is a common and disabling condition that represents a potentially attractive target for regenerative therapy. Stem cells from a wide range of origins have been investigated in studies using animal models of stroke, with evidence that neural or mesenchymal cells migrate to the site of ischemic injury after intravascular or intraparenchymal delivery, and that a proportion of cells survive and differentiate into cells with characteristics of neurons or glia. In some studies there is evidence of electrical function of transplanted cells. Some studies report improvements in neurological function with cell implantation even when undertaken up to 30 days after the stroke is induced. Few clinical trials have been undertaken to date, with two studies of a teratocarcinoma-derived cell line delivered by direct brain injection, and two of bone-marrow derived mesenchymal stem cells delivered intravascularly. Ongoing trials of other cell lines are exploring safety. There are considerable difficulties in designing future efficacy trials, some being generic to the field of regenerative treatment in stroke, and some that are specific to stem cells or their mode of delivery.

Will Stem Cell Open up the New Realms of Neurointervention?

In June, I heard on the news about the world's first stem cell medication. The news said that a cardiac stem cell therapy was expected to be approved for use at hospitals. The approval will be the first of its kind in the world to allow the use of this form of treatment. The nation's drug safety agency said that a stem cell medication for treating heart attack victims, passed all the required safety and quality tests. The vendor said that the cardiac stem cell therapy could improve ventricular contraction in patients with refractory post-infarct heart failure. They also said that the phase III study is underway on the stem cell therapy for recovery of brain [1]. Before Dr. Woo-Suk Hwang made ethical problems in his research, the stem cell therapy had had a high public attention 5 years ago. The hard controversy about ethical problems about embryonic stem cell and the intangible achievement led to draw public attention away from stem cell therapy. However, many efforts have been made to use the stem cells driven from umbilical cord blood or bone marrow instead of embryonic stem cell. Somatic cells, such as fibroblasts extracted from the patient's own body, can be reprogrammed to pluripotent stem cells by the introduction of transcription factors. These induced pluripotent stem cells are then differentiated to specific neuron types for transplantation with this technology. Patient-specific cells can be produced without the need for immunosuppressive treatment after transplantation. Then, the ethical issue with the use of human embryonic stem cells can be avoided [2]. Results of many basic researches bring us much closer to the day when clinical grade stem cells might be available. Stem cell therapy offers a remarkable potential for the recovery of brain function after stroke, and treatment of stroke using stem cell is a challenge that is worthy of high expectations. Nowadays, we can easily find out a lot of researches about stem cell for stroke recovery from Google or Pubmed search engine. The delivery of stem cell to targeting an area is the cause that neurointerventionists should be concerned about the stem cell therapy in stroke. There are multimodal delivery methods from stereotactic injection to intra-arterial routes. In view of the results so far achieved, intra-arterial delivery of stem cells is performed via the catheter that is traced though the feeding artery to the target area. This method will have a chance to take up as a commercialize method, and can have benefits than other delivery methods. Stereotactic injection is more invasive than intra-arterial delivery. In addition, targeted intra-arterial transplantation of stem cells to the injured brain is more effective than intravenous administration [3]. Intra-arterial delivery can be disseminated into specific affected areas of the brain through the arterial system. Delivered stem cells differentiate into neurons, and migrate toward the ischemic lesion in brain [4]. There is growing evidence that stem cells can induce functional improvement by mechanisms other than neuronal replacement. Products from transplanted stem cells can induce modulation of inflammation, promotion of angiogenesis, and neuroprotection [5]. The catheterization safely in intracranial arteries is the unique business of neurointerventionists. Therefore, I think that neurointerventionists are most suitable to perform the intra-arterial injection of stem cell to a lesion in brain. However, stem cell therapy is not always wonderful, and is just beginning to be translated into the clinical realm. In order to apply into clinical fields, several items have to be investigated. Most importantly, the safety and efficacy should be confirmed. It should be proved whether intra-arterial injection of neural stem cells using a catheter technique causes microembolic strokes or not. The risk for tumor formation also should be eliminated. To bring the stem cells therapy much closer to clinical applications, several clinical studies using intra-arterial infusion of non-NSCs or MSCs in patients with stroke are ongoing or planned (www.clinicaltrials.gov). It is certain that the stem cell therapy for brain recovery is just beginning to be translated into the clinical realm and we are entering a new era in which neurointerventionist can work. In order to play a leading role in stem cell therapy, we should be concerned about this item and actively participate in the stage of basic and clinical research.

脳卒中における再生医療の展望(<特集>明日の脳神経外科を拓く神経科学)

われわれは,1990年代初期から,各種細胞(幹細胞を含む)を用いた神経再生治療へ向けた基礎研究を継続してきた.近年は,骨髄間葉系幹細胞(mesenchymal stem cell:MSC)をドナー細胞とした神経再生研究に注目し,MSCは経静脈内投与で脳梗塞に対して著明な治療効果が認められるという基礎研究結果を多数報告してきた.これらの基礎研究結果に基づき,2007年1月より自己血清で培養した自己MSCを脳梗塞亜急性期の患者に対して静脈内投与を行い,安全性と治療効果について検討した.

Regulation of neural stem cell by bone morphogenetic protein (BMP) signaling during brain development

Neurogenesis is the process in which neurons are generated from neural stem/progenitor cells (NSCs/NPCs). It involves the proliferation and neuronal fate specification/differentiation of NSCs, as well as migration, maturation and functional integration of the neuronal progeny into neuronal network. NSCs exhibit the two essential properties of stem cells: self-renewal and multipotency. Contrary to previous dogma that neurogenesis happens only during development, it is generally accepted now that neurogenesis can take place throughout life in mammalian brains. This raises a new therapeutic potential of applying stem cell therapy for stroke, neurodegenerative diseases and other diseases. However, the maintenance and differentiation of NSCs/NPCs are tightly controlled by the extremely intricate molecular networks. Uncovering the underlying mechanisms that drive the differentiation, migration and maturation of specific neuronal lineages for use in regenerative medicine is, therefore, crucial for the application of stem cell for clinical therapy as well as for providing insight into the mechanisms of human neurogenesis. Here, we focus on the role of bone morphogenetic protein (BMP) signaling in NSCs during mammalian brain development.

Affirmative Action of Osteopontin on Endothelial Progenitors

Gender differences in susceptibility to coronary heart disease have been firmly established: the incidence of various manifestations of coronary atherosclerosis is less in premenopausal women than age-matched men. The protective role of estrogen covers a broad range of mechanisms including improvement of endothelial regeneration after arterial injury. Mediated primarily by the estrogen receptor alpha (ERα), 17β-estradiol (E2) stimulates migration and proliferation of endothelium. This effect involves among others, eNOS activity,1 prostacyclin, endothelin, bFGF,2 and VEGF-R2 signaling.3 Estrogen also stimulates the recruitment of endothelial progenitor cells (EPCs), which in experimental and emerging clinical studies appear to be important effectors of endothelium repair (for review see Besler et al4). In rodents, E2 increases the number of circulating EPCs and enhances their adherence and homing to the region of vascular damage. This process is ERα dependent and EPCs are believed to play a nonredundant role in the E2 enhanced reendothialization.1 Likewise, in premenopausal women a higher number of circulating EPCs is found when compared to age-matched men. The level of circulating EPCs synchronizes with menstrual cycle and is the highest during the fertile period. In addition, male EPCs showed a lower adherence capacity as compared to premenopausal female EPCs, an effect that was abolished by E2 supplementation.5 See accompanying article on page 2131 The presumed clinical relevance of EPC recruitment, for instance in restenosis, is underscored by …

Stem cell therapy in stroke.

Recent work has focused on cell transplantation as a therapeutic option following ischemic stroke, based on animal studies showing that cells transplanted to the brain not only survive, but also lead to functional improvement. Neural degeneration after ischemia is not selective but involves different neuronal populations, as well as glial and endothelial cell types. In models of stroke, the principal mechanism by which any improvement has been observed, has been attributed to the release of trophic factors, possibly promoting endogenous repair mechanisms, reducing cell death and stimulating neurogenesis and angiogenesis. Initial human studies indicate that stem cell therapy may be technically feasible in stroke patients, however, issues still need to be addressed for use in human subjects.

バイオ素材による創薬とＤＤＳ 骨髄由来中胚葉系幹細胞による脳梗塞の治療

バイオ素材による創薬とＤＤＳ 骨髄由来中胚葉系幹細胞による脳梗塞の治療

Current Concepts in Adult Stem Cell Therapy for Stroke

Acute ischemic stroke causes a disturbance of neuronal circuitry and disruption of the blood-brain-barrier that can lead to functional disabilities. At present, thrombolytic therapy inducing recanalization of the occluded vessels in the cerebral infarcted area is a commonly used therapeutic strategy. However, only a minority of patients have timely access to this kind of therapy. Therefore, finding other techniques to effectively treat stroke patients is an important research goal. Stem cell therapies, such as adult stem cell transplantation, are promising strategies for the treatment of stroke. Preclinical experimental studies have included the application of human stem cells from various sources including the brain, bone marrow, umbilical cord, and adipose tissue. This review provides an update on current preclinical cell-therapies for stroke, focusing on stem cells derived from adult sources.

Adult stem cell therapy in stroke

Acute cerebral infarction causes irreversible locally restricted loss of the neuronal circuitry and supporting glial cells with consecutive functional deficits and disabilities. The currently available and effective therapy targets fast vessel recanalization accompanied by symptomatic measures. Research activities focusing on stem cells, which represent a promising source for organotypic cell replacement and functional recovery after stroke, have gained momentum in recent years, making regenerative cell-based therapies a much more feasible realistic approach. This review provides an update about preclinical and clinical cell-based studies in stroke focusing on stem cells derived from the adult central nervous and hematopoetic systems. Endogenous neural stem cells, which have been shown to reside throughout life in the central nervous system, have the capacity to replace lost neurons in models for numerous disorders, including cerebral ischemia. Considering adult neural stem cell transplantation as a regenerative strategy after stroke, progress has been made in isolating human adult neural stem cells and demonstrating the feasibility of autologous neural stem cell transplantation. An increasing number of studies provide evidence that hematopoietic stem cells, either after stimulation of endogenous stem cell pools or after exogenous hematopoietic stem cell application (transplantation), improve functional outcome after ischemic brain lesions. Various underlying mechanisms such as transdifferentiation into neural lineages, neuroprotection through trophic support, and cell fusion have been deciphered. Many preclinical studies employing adult stem cell-based strategies hold great promise. For endogenous approaches the correlate of cell replacement underlying functional improvement needs to be demonstrated. Transplantation approaches on the experimental level need further development before clinical application can be considered.