CD133 Identifies a Human Bone Marrow Stem/Progenitor Cell Sub-population With a Repertoire of Secreted Factors That Protect Against Stroke

Department of Medicine, Stem Cell Core, University of Vermont, Colchester, Vermont 05446, USA.
Molecular Therapy (Impact Factor: 6.23). 09/2009; 17(11):1938-47. DOI: 10.1038/mt.2009.185
Source: PubMed


The reparative properties of bone marrow stromal cells (BMSCs) have been attributed in part to the paracrine action of secreted factors. We isolated typical human BMSCs by plastic adherence and compared them with BMSC sub-populations isolated by magnetic-activated cell sorting against CD133 (CD133-derived BMSCs, CD133BMSCs) or CD271 [p75 low-affinity nerve growth factor receptor (p75LNGFR), p75BMSCs]. Microarray assays of expressed genes, and enzyme-linked immunosorbent assays (ELISAs) of selected growth factors and cytokines secreted under normoxic and hypoxic conditions demonstrated that the three transit-amplifying progenitor cell populations were distinct from one another. CD133BMSC-conditioned medium (CdM) was superior to p75BMSC CdM in protecting neural progenitor cells against cell death during growth factor/nutrient withdrawal. Intracardiac (arterial) administration of concentrated CD133BMSC CdM provided neuroprotection and significantly reduced cortical infarct volumes in mice following cerebral ischemia. In support of the paracrine hypothesis for BMSC action, intra-arterial infusion of CD133BMSC CdM provided significantly greater protection against stroke compared with the effects of CD133BMSC (cell) administration. CdM from CD133BMSCs also provided superior protection against stroke compared with that conferred by CdM from p75BMSCs or typically isolated BMSCs. CD133 identifies a sub-population of nonhematopoietic stem/progenitor cells from adult human bone marrow, and CD133BMSC CdM may provide neuroprotection for patients with stroke.

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Available from: Joni Ylostalo, Apr 15, 2014
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    • "All BM stem cell sub-populations are in this way included , and several may be beneficial. Multipotent mesenchymal stromal cells (MSCs) are important[32,33], but CD34-positive haematopoetic stem cells also have reparative potential[34,35], as do CD133-positive stem cells[36,37]; other less well-defined sub-populations including Stro-1 positive cells3839404142may also be valuable434445. Cell selection obviously excludes the majority of cell types; but the available evidence suggests that there is no reason to exclude any specific BM stem cell sub-population; indeed in some circumstances, unfiltered cells have better reparative potential than MSCs[46]. "
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    ABSTRACT: Background We have recently completed an evaluation of the safety and feasibility of intravenous delivery of autologous bone marrow in patients with progressive multiple sclerosis (MS). The possibility of repair was suggested by improvement in the neurophysiological secondary outcome measure seen in all participants. The current study will examine the efficacy of intravenous delivery of autologous marrow in progressive MS. Laboratory studies performed in parallel with the clinical trial will further investigate the biology of bone marrow-derived stem cell infusion in MS, including mechanisms underlying repair. Methods/design A prospective, randomised, double-blind, placebo-controlled, stepped wedge design will be employed at a single centre (Bristol, UK). Eighty patients with progressive MS will be recruited; 60 will have secondary progressive disease (SPMS) but a subset (n = 20) will have primary progressive disease (PPMS). Participants will be randomised to either early or late (1 year) intravenous infusion of autologous, unfractionated bone marrow. The placebo intervention is infusion of autologous blood. The primary outcome measure is global evoked potential derived from multimodal evoked potentials. Secondary outcome measures include adverse event reporting, clinical (EDSS and MSFC) and self-assessment (MSIS-29) rating scales, optical coherence tomography (OCT) as well as brain and spine MRI. Participants will be followed up for a further year following the final intervention. Outcomes will be analysed on an intention-to-treat basis. Discussion Assessment of bone marrow-derived Cellular Therapy in progressive Multiple Sclerosis (ACTiMuS) is the first randomised, placebo-controlled trial of non-myeloablative autologous bone marrow-derived stem cell therapy in MS. It will determine whether bone marrow cell therapy can, as was suggested by the phase I safety study, improve conduction in multiple central nervous system pathways affected in progressive MS. Furthermore, laboratory studies performed in parallel with the clinical trial will inform our understanding of the cellular pharmacodynamics of bone marrow infusion in MS patients and the mechanisms underlying cell therapy. Trial Registration ISRCTN27232902 Registration date 11/09/2012. NCT01815632 Registration date 19/03/2013
    Full-text · Article · Dec 2015 · Trials
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    • "Correspondence: Nasser Aghdami, MD, PhD, Department of Regenerative Medicine at Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, The Academic Center for Education, Culture and Research (ACECR), Tehran, Iran. E-mail: Cytotherapy, 2015; 17: 232e241 (Received 16 May 2014; accepted 26 October 2014) with the potential for angiogenesis, neuroprotective and neurotrophic factor secretion [17], a robust capability for proliferation and less immunogenicity potency [18]. Also, purified CD133 þ cells that are free from leukocytes and their progenitors can significantly decrease high inflammatory reactions at graft sites. "
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    ABSTRACT: Background aims: Recent studies have proposed that cellular transplantation may have some regenerative and functional efficacy in the treatment of cerebral palsy (CP); however, much remains to be understood regarding its safety, feasibility and efficacy. This study was initiated to evaluate the safety of autologous bone marrow-derived CD133(+) cell intrathecal injection. Methods: Children (n = 12), aged 4 to 12 years, who were diagnosed with different types of CP underwent BM aspiration. CD133(+) cells were enriched from the BM samples and intrathecally injected. The Gross Motor Function Measure (GMFM-66), Gross Motor Function Classification System (GMFCS), UK FIM+FAM, Functional Independence Measure (FIM) and Functional Assessment Measure (FAM) were assessed at baseline and 6 months after the procedure. Patients' ability to balance was measured by the Berg Balance Scale (BBS), and severity of spasticity was evaluated by the Modified Ashworth Scale. Magnetic resonance imaging was done at baseline and 6 months after therapy. This study was registered in (NCT01404663). Results: There were no adverse events detected by clinical and laboratory tests or imaging studies, with the exception of a seizure in 1 patient. A significant improvement was observed 6 months after cell transplantation versus baseline according to GMFM, GMFCS, FIM+FAM, Ashworth Scale, and BBS outcomes. Conclusions: Subarachnoid injection of CD133-positive enriched bone marrow progenitor cells in children with CP is a safe approach. The results suggest a possible short-term improvement in neurological function.
    Full-text · Article · Nov 2014 · Cytotherapy
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    • "Cerebral ischemia infarction—1 day—IC/intracardiac (LV) injection immunodeficient mice (i) Hu-BM-MSC (ii) Hu-BM-CD133 (iii) Hu-BM-p75 (iv) Hu-fibro Reduced cortical infarct volume (huBM-CD133-CM < huBM-MSC-CM < hufibroCM < huBM-p75CM) [25] Fluid percussion-TBI—direct IV jugular vein Male SD rat Hu-BM-MSC Reduced neuron loss, A, neuron A, infarction volume, and motor deficit Increased VEGF(+) cells [26] "
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    ABSTRACT: Background. Stem cell-derived conditioned medium has a promising prospect to be produced as pharmaceuticals for regenerative medicine. Objective. To investigate various methods to obtain stem cell-derived conditioned medium (CM) to get an insight into their prospect of application in various diseases. Methods. Systematic review using keywords "stem cell" and "conditioned medium" or "secretome" and "therapy." Data concerning treated conditions/diseases, type of cell that was cultured, medium and supplements to culture the cells, culture condition, CM processing, growth factors and other secretions that were analyzed, method of application, and outcome were noted, grouped, tabulated, and analyzed. Results. Most of CM using studies showed good results. However, the various CM, even when they were derived from the same kind of cells, were produced by different condition, that is, from different passage, culture medium, and culture condition. The growth factor yields of the various types of cells were available in some studies, and the cell number that was needed to produce CM for one application could be computed. Conclusion. Various stem cell-derived conditioned media were tested on various diseases and mostly showed good results. However, standardized methods of production and validations of their use need to be conducted.
    Full-text · Article · Sep 2014 · BioMed Research International
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