Neuronal stem cell-drug interactions : a systematic review and meta-analysis

Stem cell therapy is a promising treatment option for neurodegenerative diseases that mostly affect geriatric patients who often suffer from comorbidities requiring multiple medications. However, not much is known about the interactions between stem cells and drugs. Here, we focus on the potential interactions between drugs used to treat the comorbidities or sequelae of neurodegenerative diseases and neuronal stem cells to reveal potential effects on drug safety and efficacy. To determine the potential effects of drugs frequently used in geriatric patients (analgesic, antibiotic, antidepressant, antidiabetic, antihyperlipidemic, and antihypertensive drugs) on neuronal stem cell differentiation and proliferation, we systematically searched PubMed to identify nonreview articles published in English in peer‐reviewed journals between January 1, 1991, and June 7, 2018. We identified 5,954 publications, of which 214 were included. Only 62 publications provided the complete data sets required for meta‐analysis. We found that antidepressants stimulated neuronal stem cell proliferation but not differentiation under physiologic conditions and increased the proliferation of stem cells in the context of stress. Several other potential interactions were identified, but the limited number of available data sets precludes robust conclusions. Although available data were in most cases insufficient to perform robust meta‐analysis, a clear interaction between antidepressants and neuronal stem cells was identified. We reveal other potential interactions requiring further experimental investigation. We recommend that future research addresses such interactions and investigates the best combination of pharmacological interventions and neuronal stem cell treatments for more efficient and safer patient care. Stem Cells Translational Medicine 2019;8:1202–121

Editorial: Neurodegenerative Diseases: Looking Beyond the Boundaries of the Brain

Neurodegenerative Diseases: Looking Beyond the Boundaries of the Brai

Skin-derived stem cells for wound treatment using cultured epidermal autografts : clinical applications and challenges

The human skin fulfills important barrier, sensory, and immune functions—all of which contribute significantly to health and organism integrity. Widespread skin damage requires immediate treatment and coverage because massive skin loss fosters the invasion of pathogens, causes critical fluid loss, and may ultimately lead to death. Since the skin is a highly immunocompetent organ, autologous transplants are the only viable approach to permanently close a widespread skin wound. Despite the development of tissue-saving autologous transplantation techniques such as mesh and Meek grafts, treatment options for extensive skin damage remain severely limited. Yet, the skin is also a rich source of stem and progenitor cells. These cells promote wound healing under physiological conditions and are potential sources for tissue engineering approaches aiming to augment transplantable tissue by generating cultured epidermal autografts (CEAs). Here, we review autologous tissue engineering strategies as well as transplantation products based on skin-derived stem cells. We further provide an overview of clinical trial activities in the field and discuss relevant translational and clinical challenges associated with the use of these products

Potential effects of commonly applied drugs on neural stem cell proliferation and viability : a hypothesis-generating systematic review and meta-analysis

Neural stem cell (NSC) transplantation is an emerging and promising approach to combat neurodegenerative diseases. While NSCs can differentiate into neural cell types, many therapeutic effects are mediated by paracrine, “drug-like” mechanisms. Neurodegenerative diseases are predominantly a burden of the elderly who commonly suffer from comorbidities and thus are subject to pharmacotherapies. There is substantial knowledge about drug-drug interactions but almost nothing is known about a potential impact of pharmacotherapy on NSCs. Such knowledge is decisive for designing tailored treatment programs for individual patients. Previous studies revealed preliminary evidence that the anti-depressants fluoxetine and imipramine may affect NSC viability and proliferation. Here, we derive a hypothesis on how commonly applied drugs, statins and antihypertensives, may affect NSC viability, proliferation, and differentiation. We conducted a systematic review and meta-analysis looking at potential effects of commonly prescribed antihypertensive and antihyperlipidemic medication on NSC function. PubMed and Web of Science databases were searched on according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Publications were assessed against a priori established selection criteria for relevancy. A meta-analysis was then performed on data extracted from publications eligible for full text review to estimate drug effects on NSC functions. Our systematic review identified 1,017 potential studies, 55 of which were eligible for full text review. Out of those, 21 were included in the qualitative synthesis. The meta-analysis was performed on 13 publications; the remainder were excluded as they met exclusion criteria or lacked sufficient data to perform a meta-analysis. The meta-analysis revealed that alpha-2 adrenoceptor agonists, an anti-hypertensive drug class [p < 0.05, 95% confidence intervals (CI) = –1.54; –0.35], and various statins [p < 0.05, 95% CI = –3.17; –0.0694] had an inhibiting effect on NSC proliferation. Moreover, we present preliminary evidence that L-type calcium channel blockers and statins, particularly lovastatin, may reduce NSC viability. Although the data available in the literature is limited, there are clear indications for an impact of commonly applied drugs, in particular statins, on NSC function. Considering the modes of action of the respective drugs, we reveal plausible mechanisms by which this impact may be mediated, creating a testable hypothesis, and providing insights into how future confirmative research on this topic may be conducted

Novel targets, treatments, and advanced models for intracerebral haemorrhage

Intracerebral haemorrhage (ICH) is the second most common type of stroke and a major cause of mortality and disability worldwide. Despite advances in surgical interventions and acute ICH management, there is currently no effective therapy to improve functional outcomes in patients. Recently, there has been tremendous progress uncovering new pathophysiological mechanisms underlying ICH that may pave the way for the development of therapeutic interventions. Here, we highlight emerging targets, but also existing gaps in preclinical animal modelling that prevent their exploitation. We particularly focus on (1) ICH aetiology, (2) the haematoma, (3) inflammation, and (4) post-ICH pathology. It is important to recognize that beyond neurons and the brain, other cell types and organs are crucially involved in ICH pathophysiology and successful interventions likely will need to address the entire organism. This review will spur the development of successful therapeutic interventions for ICH and advanced animal models that better reflect its aetiology and pathophysiology

Re-thinking the Etiological Framework of Neurodegeneration

Neurodegenerative diseases are among the leading causes of disability and death worldwide. The disease-related socioeconomic burden is expected to increase with the steadily increasing life expectancy. In spite of decades of clinical and basic research, most strategies designed to manage degenerative brain diseases are palliative. This is not surprising as neurodegeneration progresses "silently" for decades before symptoms are noticed. Importantly, conceptual models with heuristic value used to study neurodegeneration have been constructed retrospectively, based on signs and symptoms already present in affected patients;a circumstance that may confound causes and consequences. Hence, innovative, paradigm-shifting views of the etiology of these diseases are necessary to enable their timely prevention and treatment. Here, we outline four alternative views, not mutually exclusive, on different etiological paths toward neurodegeneration. First, we propose neurodegeneration as being a secondary outcome of a primary cardiovascular cause with vascular pathology disrupting the vital homeostatic interactions between the vasculature and the brain, resulting in cognitive impairment, dementia, and cerebrovascular events such as stroke. Second, we suggest that the persistence of senescent cells in neuronal circuits may favor, together with systemic metabolic diseases, neurodegeneration to occur. Third, we argue that neurodegeneration may start in response to altered body and brain trophic interactions established via the hardwire that connects peripheral targets with central neuronal structures or by means of extracellular vesicle (E\-mediated communication. Lastly, we elaborate on how lifespan body dysbiosis may be linked to the origin of neurodegeneration. We highlight the existence of bacterial products that modulate the gut-brain axis causing neuroinflammation and neuronal dysfunction. As a concluding section, we end by recommending research avenues to investigate these etiological paths in the future. We think that this requires an integrated, interdisciplinary conceptual research approach based on the investigation of the multimodal aspects of physiology and pathophysiology. It involves utilizing proper conceptual models, experimental animal units, and identifying currently unused opportunities derived from human data. Overall, the proposed etiological paths and experimental recommendations will be important guidelines for future cross-discipline research to overcome the translational roadblock and to develop causative treatments for neurodegenerative diseases

Recent progress in translational research on neurovascular and neurodegenerative disorders

The already established and widely used intravenous application of recombinant tissue plasminogen activator as a re-opening strategy for acute vessel occlusion in ischemic stroke was recently added by mechanical thrombectomy, representing a fundamental progress in evidence-based medicine to improve the patient’s outcome. This has been paralleled by a swift increase in our understanding of pathomechanisms underlying many neurovascular diseases and most prevalent forms of dementia. Taken together, these current advances offer the potential to overcome almost two decades of marginally successful translational research on stroke and dementia, thereby spurring the entire field of translational neuroscience. Moreover, they may also pave the way for the renaissance of classical neuroprotective paradigms. This review reports and summarizes some of the most interesting and promising recent achievements in neurovascular and dementia research. It highlights sessions from the 9th International Symposium on Neuroprotection and Neurorepair that have been discussed from April 19th to 22nd in Leipzig, Germany. To acknowledge the emerging culture of interdisciplinary collaboration and research, special emphasis is given on translational stories ranging from fundamental research on neurode- and -regeneration to late stage translational or early stage clinical investigations

New mechanistic insights, novel treatment paradigms, and clinical progress in cerebrovascular diseases

The past decade has brought tremendous progress in diagnostic and therapeutic options for cerebrovascular diseases as exemplified by the advent of thrombectomy in ischemic stroke, benefitting a steeply increasing number of stroke patients and potentially paving the way for a renaissance of neuroprotectants. Progress in basic science has been equally impressive. Based on a deeper understanding of pathomechanisms underlying cerebrovascular diseases, new therapeutic targets have been identified and novel treatment strategies such as pre- and post-conditioning methods were developed. Moreover, translationally relevant aspects are increasingly recognized in basic science studies, which is believed to increase their predictive value and the relevance of obtained findings for clinical application.This review reports key results from some of the most remarkable and encouraging achievements in neurovascular research that have been reported at the 10th International Symposium on Neuroprotection and Neurorepair. Basic science topics discussed herein focus on aspects such as neuroinflammation, extracellular vesicles, and the role of sex and age on stroke recovery. Translational reports highlighted endovascular techniques and targeted delivery methods, neurorehabilitation, advanced functional testing approaches for experimental studies, pre-and post-conditioning approaches as well as novel imaging and treatment strategies. Beyond ischemic stroke, particular emphasis was given on activities in the fields of traumatic brain injury and cerebral hemorrhage in which promising preclinical and clinical results have been reported. Although the number of neutral outcomes in clinical trials is still remarkably high when targeting cerebrovascular diseases, we begin to evidence stepwise but continuous progress towards novel treatment options. Advances in preclinical and translational research as reported herein are believed to have formed a solid foundation for this progress

Visualisierung von Zelltod nach experimentellem Schlaganfall in der Maus

Introduction: Cell death is one of the pathophysiological hallmarks after stroke. Markers to image death of brain cells in vivo are highly desirable. One of the candidate targets is phosphatidylserine (PS). Where-as PS is usually located on the inner leaflet of the plasma membrane bilayer facing the cytosol, it is translocated to the surface of the cell during cell death. This makes PS accessible for markers based on Annexin A5 (AnxA5) characterized by a high affinity and specific binding to PS. The aim of this thesis was to investigate whether AnxA5 can be used to specifically visualize cell death of brain cells after ex-perimental stroke. Methodology: In this thesis, AnxA5 was explored using three different approaches. First, we investigat-ed a fluorescently labeled AnxA5 for in vivo and ex vivo near-infrared fluorescence imaging in experi-mental stroke in the mouse. We compared it to a non-binding control of AnxA5 and to other established cell death markers. In the second study, we evaluated a dual-labeled AnxA5 in the same animal model using single-photon emission computed tomography (SPECT), ex vivo activity measurements, and auto-radiography. As a positive control, we used ethanol- induced cell death in the femur muscle. In the third study, we developed a long-circulating version of AnxA5, called XTEN-AnxA5. We examined its binding affinity using camptothecin-induced cell death in Jurkat T cells and specific accumulation inside chemo-therapy-induced cell death in tumors. Results: We showed that fluorescently labeled AnxA5 can be used to visualize cell death after experi-mental stroke in vivo. Only for functional, but not for non- binding AnxA5 control, increased signal intensi-ties in the ipsilateral compared with contralateral hemisphere were found. AnxA5 specifically bound to dead or dying cells as confirmed by immunohistochemistry where the vast majority of cells were also positive for other cell death markers. However, we did not detect dual-labeled AnxA5 in the brain using SPECT, whereas it was observed in ethanol-induced cell death in the femur muscle. Our newly devel- oped long-circulating XTEN-AnxA5 prolonged blood half-life to about 1 h and improved further imaging properties. We showed that XTEN-AnxA5 bound specifically to dead or dying cells in culture and dis-played an increased accumulation inside the tumors compared to wild-type AnxA5. Conclusions: Whereas AnxA5 seems to bind specifically to dead or dying cells, its applicability for brain imaging needs to be further investigated using compounds designed to overcome the blood-brain barrier and reach their target.Einleitung: Zelltod ist eines der pathophysiologischen Ereignisse nach Schlaganfall. Aus diesem Grund ist es erstrebenswert, Marker zur Bildgebung von Zelltod in vivo zu finden. Als mögliches Target kommt Phosphatidylserine (PS) in Frage. Während sich PS in gesunden Zellen auf der Innenseite der Plasma-membran dem Zytosol zugewandt befindet, wird es auf die Zelloberfläche transloziert, sobald eine Zelle stirbt. Auf diese Weise wird PS für Annexin A5 (AnxA5)-basierte Marker zugänglich, die dieses mit hoher Affinität und Spezifität binden. Ziel dieser Doktorarbeit war es, zu untersuchen, ob AnxA5 zur spezifi-schen Bildgebung von Zelltod nach experimentellem Schlaganfall eingesetzt werden kann. Methodik: In dieser Arbeit wurde AnxA5 in drei verschiedenen Studien erforscht. In der ersten Studie untersuchten wir ein fluoreszenz-markiertes AnxA5 zur In-vivo- und Ex-vivo-Nah-Infrarot- Fluoreszenzbildgebung im Schlaganfallmodell der Maus. Dazu verglichen wir es mit einer nicht-bindenden AnxA5-Kontrollsubstanz und anderen etablierten Zelltodmarkern. In der zweiten Studie evaluierten wir ein zweifach markiertes AnxA5 im gleichen Tiermodell unter Verwendung von Einzelphotonen- Emissionscomputertomographie (SPECT), Ex-vivo-Aktivitätsmessungen und Autoradiographie. Zur Posi-tivkontrolle diente Äthanol-induzierter Zelltod im Oberschenkelmuskel. Schließlich entwickelten wir in der dritten Studie ein lang zirkulierendes AnxA5, das so genannte XTEN-AnxA5. Wir untersuchten seine Bin-dungsaffinität mittels Camptothecin induziertem Zelltod in Jurkat-T-Zellen und die spezifische Anreiche-rung des Moleküls in Tumoren nach durch Chemotherapie induziertem Zelltod. Ergebnisse: Wir konnten nachweisen, dass fluoreszenz-markiertes AnxA5 nach experimentellem Schlaganfall zur In-vivo- Zelltodbildgebung verwendet werden kann. Nur bei funktionellem, aber nicht bei der nicht-bindendem AnxA5-Kontrolle, konnten erhöhte Signalintensitäten in der geschädigten im Ver-gleich zur nicht geschädigten Gehirnhälfte gefunden werden. Tote oder sterbende Zellen wurden spezi-fisch von AnxA5 gebunden, was durch Immunhistochemie bestätigt wurde, wobei auch andere Zelltod-marker die Mehrzahl dieser Zellen markierten. Jedoch waren wir nicht in der Lage mit SPECT zweifach markiertes AnxA5 im Schlaganfall festzustellen, wohingegen es bei Äthanol-induziertem Zelltod im Ober-schenkelmuskel nachgewiesen werden konnte. Unser neu entwickeltes lang zirkulierendes XTEN-AnxA5 verlängerte die Bluthalbwertzeit auf etwa eine Stunde und verbesserte weitere Bildgebungseigenschaften. Tote oder sterbende Zellen in Kultur wurden spezifisch von XTEN-AnxA5 gebunden und wir erreichten eine stärkere Anreicherung von XTEN-AnxA5 im Vergleich zu Wildtyp-AnxA5 in Tumoren. Schlussfolgerung: Während AnxA5 scheinbar spezifisch an tote oder sterbende Zellen bindet, muss seine Eignung für Bildgebung im Gehirn unter Verwendung von Substanzen, die so ausgelegt sind, die Bluthirnschranke zu überwinden und das Zielmolekül zu erreichen, weiter untersucht werden