Hung Nguyen

Menstrual Blood-Derived Stem Cells: In Vitro and In Vivo Characterization of Functional Effects.

Accumulating evidence has demonstrated that menstrual blood stands as a viable source of stem cells. Menstrual blood-derived stem cells (MenSCs) are morphologically and functionally similar to cells directly extracted from the endometrium, and present dual expression of mesenchymal and embryonic cell markers, thus becoming interesting tools for regenerative medicine. Functional reports show higher proliferative and self-renewal capacities than bone marrow-derived stem cells, as well as successful differentiation into hepatocyte-like cells, glial-like cells, endometrial stroma-like cells, among others. Moreover, menstrual blood stem cells may be used with increased efficiency in reprogramming techniques for induced Pluripotent Stem cell (iPS) generation. Experimental studies have shown successful treatment of stroke, colitis, limb ischemia, coronary disease, Duchennes muscular atrophy and streptozotocin-induced type 1 diabetes animal models with MenSCs. As we envision an off-the-shelf product for cell therapy, cryopreserved MenSCs appear as a feasible clinical product. Clinical applications, although still very limited, have great potential and ongoing studies should be disclosed in the near future.

Stem Cell-Induced Biobridges as Possible Tools to Aid Neuroreconstruction after CNS Injury

Notch-induced mesenchymal stromal cells (MSCs) mediate a distinct mechanism of repair after brain injury by forming a biobridge that facilitates biodistribution of host cells from a neurogenic niche to the area of injury. We have observed the biobridge in an area between the subventricular zone and the injured cortex using immunohistochemistry and laser capture. Cells in the biobridge express high levels of extracellular matrix metalloproteinases (MMPs), specifically MMP-9, which co-localized with a trail of MSCs graft. The transplanted stem cells then become almost undetectable, being replaced by newly recruited host cells. This stem cell-paved biobridge provides support for distal migration of host cells from the subventricular zone to the site of injury. Biobridge formation by transplanted stem cells seems to have a fundamental role in initiating endogenous repair processes. Two major stem cell-mediated repair mechanisms have been proposed thus far: direct cell replacement by transplanted grafts and bystander effects through the secretion of trophic factors including fibroblast growth factor 2 (FGF-2), epidermal growth factor (EGF), stem cell factor (SCF), erythropoietin, and brain-derived neurotrophic factor (BDNF) among others. This groundbreaking observation of biobridge formation by transplanted stem cells represents a novel mechanism for stem cell mediated brain repair. Future studies on graft-host interaction will likely establish biobridge formation as a fundamental mechanism underlying therapeutic effects of stem cells and contribute to the scientific pursuit of developing safe and efficient therapies not only for traumatic brain injury but also for other neurological disorders. The aim of this review is to hypothetically extend concepts related to the formation of biobridges in other central nervous system disorders.

Growth factor therapy sequesters inflammation in affording neuroprotection in cerebrovascular diseases

ABSTRACT Introduction: In recent years, accumulating evidence has demonstrated the key role of inflammation in the progression of cerebrovascular diseases. Inflammation can persist over prolonged period of time after the initial insult providing a wider therapeutic window. Despite the acute endogenous upregulation of many growth factors after the injury, it is not sufficient to protect against inflammation and to regenerate the brain. Therapeutic approaches targeting both dampening inflammation and enhancing growth factors are likely to provide beneficial outcomes in cerebrovascular disease. Areas covered: In this mini review, we discuss major growth factors and their beneficial properties to combat the inflammation in cerebrovascular diseases. Emerging biotechnologies which facilitate the therapeutic effects of growth factors are also presented in an effort to provide insights into the future combination therapies incorporating both central and peripheral abrogation of inflammation. Expert commentary: Many studies discussed in this review have demonstrated the therapeutic effects of growth factors in treating cerebrovascular diseases. It is unlikely that one growth factor can be used to treat these complex diseases. Combination of growth factors and anti-inflammatory modulators may clinically improve outcomes for patients. In particular, transplantation of stem cells may be able to achieve both goals of modulating inflammation and upregulating growth factors. Large preclinical studies and multiple laboratory collaborations are needed to advance these findings from bench to bedside.

Histopathological and Behavioral Assessments of Aging Effects on Stem Cell Transplants in an Experimental Traumatic Brain Injury

Traumatic brain injury (TBI) displays cognitive and motor symptoms following the initial injury which can be exacerbated by secondary cell death. Aging contributes significantly to the morbidity of TBI, with higher rates of negative neurological and behaviors outcomes. In the recent study, young and aged animals were injected intravenously with human adipose-derived mesenchymal stem cells (hADSCs) (Tx), conditioned media (CM), or vehicle (unconditioned media) following TBI. The beneficial effects of hADSCs were analyzed using various molecular and behavioral techniques. More specially, DiR-labeled hADSCs were used to observe the biodistribution of the transplanted cells. In addition, a battery of behavior tests was conducted to evaluate the neuromotor function for each treatment group and various regions of the brain were analyzed utilizing Nissl, hematoxylin and eosin (H&E), and human nuclei (HuNu) staining. Finally, flow cytometry was also performed to determine the levels of various proteins in the spleen. Here, we discuss the protocols for characterizing the histopathological and behavioral effects of transplanted stem cells in an animal model of TBI, with an emphasis on the role of aging in the therapeutic outcomes.

Stem Cell-Paved Biobridge: A Merger of Exogenous and Endogenous Stem Cells Toward Regenerative Medicine in Stroke

Stroke is a significant unmet clinical need with therapeutic options limited to tissue-type plasminogen activator (tPA), which has a small therapeutic window and risk for hemorrhagic transformation. Stroke is a multiphasic disease with a complex pathology. After the initial insult, a cascade of events occur causing secondary cell death and the expansion of the penumbra. The major contributing factors to this secondary cell death are depletion of growth factors, neuroinflammation, and disruption of the neurovascular unit. There is a need for more innovative and effective therapies that can target the diverse pathological consequences of stroke. To this end, stem cell therapy is a promising approach for stroke. Pre-clinical studies have demonstrated the potential of stem cells for treating neurological disorders, including stroke. Here, we discuss diverse stem cell types which have generated encouraging results for advancing to the clinic. Then, we examine the mechanisms of action of stem cells—cell replacement, by stander effect, and a novel biobridge concept advanced by our laboratory. These mechanisms work in concert to afford the neuroprotection and neuroregeneration after stroke. We envision that an in-depth understanding of the benefits and drawbacks of various stem cells and their mechanisms of action will guide the translational entry of stem cell therapy from the laboratory into the clinical setting.

Stem cell therapy for neurological disorders: A focus on aging

Age-related neurological disorders continue to pose a significant societal and economic burden. Aging is a complex phenomenon that affects many aspects of the human body. Specifically, aging can have detrimental effects on the progression of brain diseases and endogenous stem cells. Stem cell therapies possess promising potential to mitigate the neurological symptoms of such diseases. However, aging presents a major obstacle for maximum efficacy of these treatments. In this review, we discuss current preclinical and clinical literature to highlight the interactions between aging, stem cell therapy, and the progression of major neurological disease states such as Parkinsons disease, Huntingtons disease, stroke, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis, and multiple system atrophy. We raise important questions to guide future research and advance novel treatment options.

Understanding the Role of Dysfunctional and Healthy Mitochondria in Stroke Pathology and Its Treatment

Stroke remains a major cause of death and disability in the United States and around the world. Solid safety and efficacy profiles of novel stroke therapeutics have been generated in the laboratory, but most failed in clinical trials. Investigations into the pathology and treatment of the disease remain a key research endeavor in advancing scientific understanding and clinical applications. In particular, cell-based regenerative medicine, specifically stem cell transplantation, may hold promise as a stroke therapy, because grafted cells and their components may recapitulate the growth and function of the neurovascular unit, which arguably represents the alpha and omega of stroke brain pathology and recovery. Recent evidence has implicated mitochondria, organelles with a central role in energy metabolism and stress response, in stroke progression. Recognizing that stem cells offer a source of healthy mitochondria—one that is potentially transferrable into ischemic cells—may provide a new therapeutic tool. To this end, deciphering cellular and molecular processes underlying dysfunctional mitochondria may reveal innovative strategies for stroke therapy. Here, we review recent studies capturing the intimate participation of mitochondrial impairment in stroke pathology, and showcase promising methods of healthy mitochondria transfer into ischemic cells to critically evaluate the potential of mitochondria-based stem cell therapy for stroke patients.

Mitochondrial targeting as a novel therapy for stroke

Stroke is a main cause of mortality and morbidity worldwide. Despite the increasing development of innovative treatments for stroke, most are unsuccessful in clinical trials. In recent years, an encouraging strategy for stroke therapy has been identified in stem cells transplantation. In particular, grafting cells and their secretion products are leading with functional recovery in stroke patients by promoting the growth and function of the neurovascular unit – a communication framework between neurons, their supply microvessels along with glial cells – underlying stroke pathology and recovery. Mitochondrial dysfunction has been recently recognized as a hallmark in ischemia/reperfusion neural damage. Emerging evidence of mitochondria transfer from stem cells to ischemic-injured cells points to transfer of healthy mitochondria as a viable novel therapeutic strategy for ischemic diseases. Hence, a more in-depth understanding of the cellular and molecular mechanisms involved in mitochondrial impairment may lead to new tools for stroke treatment. In this review, we focus on the current evidence of mitochondrial dysfunction in stroke, investigating favorable approaches of healthy mitochondria transfer in ischemic neurons, and exploring the potential of mitochondria-based cellular therapy for clinical applications. This paper is a review article. Referred literature in this paper has been listed in the references section. The data sets supporting the conclusions of this article are available online by searching various databases, including PubMed.

Growth Factors and Cerebrovascular Diseases

Acute upregulation of growth factors in the brain ensues after onset of cerebrovascular disease, which may indicate a compensatory regenerative process mounted by the injured brain. The increased presence of these therapeutic molecules in the brain under pathologic conditions implicates their key role in modulating brain homeostasis that may involve affording pleiotropic properties, including neurogenic, angiogenic, anti-inflammatory, and antiapoptotic effects. During the progression of these diseases, however, downregulation of growth factors has been detected, indicating the need to replenish these therapeutic molecules as a potential treatment to halt this equally debilitating secondary cell death. We discuss here major growth factors and their beneficial activity in cerebrovascular diseases. Recent developments in emerging technologies for growth factor delivery into the central nervous system are also introduced in this chapter.

Stem Cell Therapy for Ischemic Stroke

Defined as a cerebrovascular disease arising from interruption of blood circulation to the brain, with the resulting damage characterized by a necrotic core enveloped within a region of hypoxic, degenerating cells, ischemic stroke remains a primary cause of death within the United States. Despite our increasing scientific knowledge regarding the pathology of stroke, our medical intervention options for patients suffering from stroke remain extremely limited. Tissue plasminogen activator (tPA) is the only FDA-approved drug shown to improve stroke. Unfortunately, in order for tPA treatment to be effective, it must be administered within 4.5 h of stroke onset. Consequentially, its therapeutic efficacy is constrained to less than 5 % of all patients suffering from ischemic stroke. One experimental therapy for stroke treatment involves the transplantation of stem cells. Stem cell transplantation has been traditionally considered to either replace dead and dying cells, or to release growth factors in affording therapeutic benefits in stroke. To date, however, the exact mechanism by which stem cell transplantation achieved neuroregeneration has not yet been precisely elucidated. Recent evidence suggests the ability of transplanted stem cells to form a biobridge connecting the area of infarction to the neurogenic niche within the brain. That stem cells can form a cellular migratory pathway between the neurogenic niche, and the stroke core and penumbra may assist and promote interaction between host brain cells and transplanted stem cells, thereby providing novel opportunities to improve the effectiveness of stem cell therapy in stroke. This chapter discusses established and emerging paradigms of stroke recovery after stem cell transplantation, in an effort to offer an in-depth understanding of safe and efficacious cell-based therapeutics for stroke.