Elizabeth Mallam

Human bone marrow-derived mesenchymal stem cells secrete brain-derived neurotrophic factor which promotes neuronal survival in vitro.

Bone marrow-derived mesenchymal stem cells (MSCs) are of therapeutic interest in a variety of neurological diseases. In this study, we wished to determine whether human MSCs secrete factors which protect cultured rodent cortical neurons from death by trophic factor withdrawal or nitric oxide (NO) exposure. Medium conditioned by MSCs attenuated neuronal death under these conditions, a process which was dependent on intact PI(3)kinase/Akt pathway signaling. Trophic withdrawal and NO exposure in cultured cortical neurons led to reduction in Akt signaling pathways, whereas NO administration activated p38 MAPkinase in neuronal cultures. Addition of MSC-conditioned medium significantly activated the PI3kinase/Akt pathway and in neurons exposed to NO, MSC-conditioned medium reduced p38 signaling. We show that MSCs secrete brain-derived neurotrophic factor (BDNF) and addition of anti-BDNF neutralising antibodies to MSC-conditioned medium attenuated its neuroprotective effect. Exposure of neurons to BDNF increased activation of Akt pathways and protected neurons from trophic factor withdrawal. These observations determine the mechanisms of neuroprotection offered by MSC-derived factors and suggest an important role for BDNF in neuronal protection.

Mesenchymal stem cell‐secreted superoxide dismutase promotes cerebellar neuronal survival

J. Neurochem. (2010) 114, 1569–1580.

Fusion between human mesenchymal stem cells and rodent cerebellar Purkinje cells

K. Kemp, D. Gordon, D. C. Wraith, E. Mallam, E. Hartfield, J. Uney, A. Wilkins and N. Scolding (2011) Neuropathology and Applied Neurobiology37, 166–178
Fusion between human mesenchymal stem cells and rodent cerebellar Purkinje cells

Inflammatory Cytokine Induced Regulation of Superoxide Dismutase 3 Expression by Human Mesenchymal Stem Cells

Increasing evidence suggests that bone marrow derived-mesenchymal stem cells (MSCs) have neuroprotective properties and a major mechanism of action is through their capacity to secrete a diverse range of potentially neurotrophic or anti-oxidant factors. The recent discovery that MSCs secrete superoxide dismutase 3 (SOD3) may help explain studies in which MSCs have a direct anti-oxidant activity that is conducive to neuroprotection in both in vivo and in vitro. SOD3 attenuates tissue damage and reduces inflammation and may confer neuroprotective effects against nitric oxide-mediated stress to cerebellar neurons; but, its role in relation to central nervous system inflammation and neurodegeneration has not been extensively investigated. Here we have performed a series of experiments showing that SOD3 secretion by human bone marrow-derived MSCs is regulated synergistically by the inflammatory cytokines TNF-alpha and IFN-gamma, rather than through direct exposure to reactive oxygen species. Furthermore, we have shown SOD3 secretion by MSCs is increased by activated microglial cells. We have also shown that MSCs and recombinant SOD are able to increase both neuronal and axonal survival in vitro against nitric oxide or microglial induced damage, with an increased MSC-induced neuroprotective effect evident in the presence of inflammatory cytokines TNF-alpha and IFN-gamma. We have shown MSCs are able to convey these neuroprotective effects through secretion of soluble factors alone and furthermore demonstrated that SOD3 secretion by MSCs is, at least, partially responsible for this phenomenon. SOD3 secretion by MSCs maybe of relevance to treatment strategies for inflammatory disease of the central nervous system.

Chemotherapy-induced mesenchymal stem cell damage in patients with hematological malignancy

Hematopoietic recovery after high-dose chemotherapy (HDC) in the treatment of hematological diseases may be slow and/or incomplete. This is generally attributed to progressive hematopoietic stem cell failure, although defective hematopoiesis may be in part due to poor stromal function. Chemotherapy is known to damage mature bone marrow stromal cells in vitro, but the extent to which marrow mesenchymal stem cells (MSCs) are damaged by HDC in vivo is largely unknown. To address this question, the phenotype and functional properties of marrow MSCs derived from untreated and chemotherapeutically treated patients with hematological malignancy were compared. This study demonstrates a significant reduction in MSC expansion and MSC CD44 expression by MSCs derived from patients receiving HDC regimens, thus implicating potential disadvantages in the use of autologous MSCs in chemotherapeutically pretreated patients for future therapeutic strategies. The clinical importance of these HDC-induced defects we have observed could be determined through prospective randomized trials of the effects of MSC cotransplantation on hematopoietic recovery in the setting of HDC with and without hematopoietic stem cell rescue.

Mesenchymal Stem Cells Restore Frataxin Expression and Increase Hydrogen Peroxide Scavenging Enzymes in Friedreich Ataxia Fibroblasts

Dramatic advances in recent decades in understanding the genetics of Friedreich ataxia (FRDA)—a GAA triplet expansion causing greatly reduced expression of the mitochondrial protein frataxin—have thus far yielded no therapeutic dividend, since there remain no effective treatments that prevent or even slow the inevitable progressive disability in affected individuals. Clinical interventions that restore frataxin expression are attractive therapeutic approaches, as, in theory, it may be possible to re-establish normal function in frataxin deficient cells if frataxin levels are increased above a specific threshold. With this in mind several drugs and cytokines have been tested for their ability to increase frataxin levels. Cell transplantation strategies may provide an alternative approach to this therapeutic aim, and may also offer more widespread cellular protective roles in FRDA. Here we show a direct link between frataxin expression in fibroblasts derived from FRDA patients with both decreased expression of hydrogen peroxide scavenging enzymes and increased sensitivity to hydrogen peroxide-mediated toxicity. We demonstrate that normal human mesenchymal stem cells (MSCs) induce both an increase in frataxin gene and protein expression in FRDA fibroblasts via secretion of soluble factors. Finally, we show that exposure to factors produced by human MSCs increases resistance to hydrogen peroxide-mediated toxicity in FRDA fibroblasts through, at least in part, restoring the expression of the hydrogen peroxide scavenging enzymes catalase and glutathione peroxidase 1. These findings suggest, for the first time, that stem cells may increase frataxin levels in FRDA and transplantation of MSCs may offer an effective treatment for these patients.

Changes in Expression of the Antioxidant Enzyme SOD3 Occur Upon Differentiation of Human Bone Marrow-Derived Mesenchymal Stem Cells In Vitro

The discovery that mesenchymal stem cells (MSCs) secrete SOD3 may help explain studies in which MSCs have direct antioxidant activities both in vivo and in vitro. SOD3 is an antioxidant enzyme that dismutes toxic free radicals produced during inflammatory processes. Therefore, MSC production and secretion of active and therapeutically significant levels of SOD3 would further support the use of MSCs as a cellular based antioxidant therapy. The aim of this study was therefore to investigate in vitro if MSC differentiation down the adipogenic, chondrogenic, and osteogenic lineages influences the expression of the antioxidant molecule SOD3. Human bone marrow MSCs and their differentiated progeny were cultured under standard conditions and both the SOD3 gene and protein expression examined. Following adipogenesis, cultures demonstrated that both SOD3 protein and gene expression are significantly increased, and conversely, following chondrogenesis SOD3 protein and gene expression is significantly decreased. Following osteogenesis there were no significant changes in SOD3 protein or gene expression. This in vitro study describes the initial characterization of SOD3 expression and secretion by differentiated MSCs. This should help guide further in vivo work establishing the therapeutic and antioxidative potential of MSC and their differentiated progeny.

Stem cells in genetic myelin disorders

The genetic myelin disorders are a range of diseases that manifest with severe neurological problems, often from infancy. It has been postulated for some time that stem cells might be an effective treatment for these disorders, primarily as agents to restore dysfunctional or lost myelin. Stem cells, however, may offer a wider range of therapeutic potential, for instance as vehicles to replace abnormal enzymes or genes, or to provide trophic support for residual CNS tissue. This article will review several of the more common genetic myelin disorders and currently available therapies, including bone marrow transplantation for adrenoleukodystrophy. Specific stem cell subtypes and their relevance to potential therapeutic use will be discussed and stem cell transplantation in animal model studies will also be reviewed.

The Use of Mesenchymal Stem Cells for treating neurodegenerative diseases

Stem cell-based therapies are increasingly emerging as hopeful therapeutic options for treating currently incurable chronic degenerative and inflammatory diseases of the central nervous system (CNS). Among the variety of different stem cell types, mesenchymal stem cells (MSCs) possess a wide range of practical features, in addition to a plethora of neuroprotective properties, which make them an attractive candidate as a potential cell therapy for a wide range of neurodegenerative disorders. Here we will discuss the suitability of MSCs for clinical use. We will also summarize the underlying mechanisms that drive their multiplicity of neuroprotective effects alongside their use in the treatment of neurodegenerative disease from the bench side to clinical trials.