Regeneration of the ischemic brain by engineered stem cells: fuelling endogenous repair processes.

Laboratory of Psychoneuroimmunology, University Medical Center Utrecht, Utrecht, The Netherlands.
Brain Research Reviews (Impact Factor: 7.82). 05/2009; 61(1):1-13. DOI: 10.1016/j.brainresrev.2009.03.003
Source: PubMed

ABSTRACT After ischemic brain injury various cell types including neurons, glia and endothelial cells are damaged and lose their function. Effective regeneration of brain tissue requires that all these cell types have to be replenished and combined to form a new functional network. Recent advances in regenerative medicine show the ability of stem cells to differentiate into various cell lineages. Several types of stem cells have been used to treat ischemic brain injury in rodent models including neuronal stem cells, mesenchymal stem cells and hematopoietic stem cells. Although these studies show promising results, it remains to be determined whether the beneficial effect of cell-based therapies in ischemic brain injury results from direct replacement of damaged cells by the transplanted cells. On the basis of the current literature we propose that neuroprotection by activation of anti-apoptotic mechanisms as well as improvement of the trophic milieu necessary for endogenous repair processes may be more important mechanisms underlying the improved functional outcome after stem cell treatment. Transplantation of native unmodified stem cells as such may not be sufficient to boost repair mechanisms provided by the endogenous stem cell population. An important aim of this review is to discuss the literature on the possible enhancement of regenerative function by combining stem cell transplantation with gene transduction into stem cells to enhance their regenerative and neuroprotective therapeutic potential. Finally, we briefly discuss the possibility of translation of this therapy to the clinic.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: There is a need for improved therapy for acquired brain injury, which has proven resistant to treatment by numerous drugs in clinical trials and continues to represent one of the leading causes of disability worldwide. Research into cell-based therapies for the treatment of brain injury is growing rapidly, but the ideal cell source has yet to be determined. Subpopulations of cells found in amniotic fluid, which is readily obtained during routine amniocentesis, can be easily expanded in culture, have multipotent differentiation capacity, are non-tumourigenic, and avoid the ethical complications associated with embryonic stem cells, making them a promising cell source for therapeutic purposes. Beneficial effects of amniotic fluid cell transplantation have been reported in various models of nervous system injury. However, evidence that amniotic fluid cells can differentiate into mature, functional neurons in vivo and incorporate into the existing circuitry to replace lost or damaged neurons is lacking. The mechanisms by which amniotic fluid cells improve outcomes after experimental nervous system injury remain unclear. However, studies reporting the expression and release of neurotrophic, angiogenic, and immunomodulatory factors by amniotic fluid cells suggest they may provide neuroprotection and (or) stimulate endogenous repair and remodelling processes in the injured nervous system. In this paper, we address recent research related to the neuronal differentiation of amniotic fluid-derived cells, the therapeutic efficacy of these cells in animal models of nervous system injury, and the possible mechanisms mediating the positive outcomes achieved by amniotic fluid cell transplantation.
    Biochemistry and Cell Biology 10/2013; 91(5):271-86. · 2.92 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Recovery after a major stroke is usually limited, but cell therapy for patients with fixed neurologic deficits is emerging. Several recent clinical trials have investigated mesenchymal stem cell (MSC) therapy for patients with ischemic stroke. We previously reported the results of a controlled trial on the application of autologous MSCs in patients with ischemic stroke with a long-term follow-up of up to 5 years (the 'STem cell Application Researches and Trials In NeuroloGy' (STARTING) study). The results from this pilot trial are challenging, but also raise important issues. In addition, there have been recent efforts to improve the safety and efficacy of MSC therapy for stroke.Methods and design: The clinical and preclinical background and the STARTING-2 study protocol are provided. The trial is a prospective, randomized, open-label, blinded-endpoint (PROBE) clinical trial. Both acute and chronic stroke patients will be selected based on clinical and radiological features and followed for 3 months after MSC treatment. The subjects will be randomized into one of two groups: (A) a MSC group (n = 40) or (B) a control group (n = 20). Autologous MSCs will be intravenously administered after ex vivo culture expansion with autologous ischemic serum obtained as early as possible, to enhance the therapeutic efficacy (ischemic preconditioning). Objective outcome measurements will be performed using multimodal MRI and detailed functional assessments by blinded observers. This trial is the first to evaluate the efficacy of MSCs in patients with ischemic stroke. The results may provide better evidence for the effectiveness of MSC therapy in patients with ischemic stroke.Trial registration: NCT01716481.
    Trials 10/2013; 14(1):317. · 2.21 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Multipotenciality and anti-inflammatory activity, the two main properties of mesenchymal stem cells (MSCs), underlie their therapeutic prospective. During the past decade numerous studies in animal models and clinical trails explored the potential of MSCs in the treatment of diseases associated with tissue regeneration and inflammatory control. Other qualities of MSCs: ready accessibility in bone marrow and fat tissue, and rapid expansion in culture make the therapeutic use of patients' own cells feasible. The prevailing belief that MSCs are non-immunogenic encouraged the use of unrelated donor cells in immune-competent recipients. The data emerging from studies performed with immune-incompatible cells in animal models for a wide-range of human diseases show, however, conflicting results and cast doubt on the immune privileged status of MSCs. Our analysis of the pre-clinical literature in this review is aimed to gain a better understanding of the therapeutic potential of immune-incompatible MSCs. Emphasis was laid on applications for enhancement of tissue repair in the absence of immune-suppressive therapy. Stem Cells 2013.
    Stem Cells 10/2013; · 7.70 Impact Factor


Available from
Aug 19, 2014