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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    • "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.
    BioMed Research International 09/2014; 2014:965849. DOI:10.1155/2014/965849 · 3.17 Impact Factor
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    • "Because serum is a source of nutrients and other ill-defined factors, we excluded it from the medium in our experiments. Bakondi et al. found that conditioned medium from immunomagnetically isolated BM-derived CD133+ cells provided significant protection against growth factor/nutrient withdrawal-induced cell death compared with serum-free medium in neural progenitor cells [57]. They also demonstrated that intra-arterial infusion of concentrated CD133+-conditioned medium provided protection against stroke in immunodeficient mice with cerebral ischemia. "
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    ABSTRACT: Stem/progenitor cells (SPCs) demonstrate neuro-regenerative potential that is dependent upon their humoral activity by producing various trophic factors regulating cell migration, growth, and differentiation. Herein, we compared the expression of neurotrophins (NTs) and their receptors in specific umbilical cord blood (UCB) SPC populations, including lineage-negative, CD34(+), and CD133(+) cells, with that in unsorted, nucleated cells (NCs). The expression of NTs and their receptors was detected by QRT-PCR, western blotting, and immunofluorescent staining in UCB-derived SPC populations (i.e., NCs vs. lineage-negative, CD34(+), and CD133(+) cells). To better characterize, global gene expression profiles of SPCs were determined using genome-wide RNA microarray technology. Furthermore, the intracellular production of crucial neuro-regenerative NTs (i.e., BDNF and NT-3) was assessed in NCs and lineage-negative cells after incubation for 24, 48, and 72 h in both serum and serum-free conditions. We discovered significantly higher expression of NTs and NT receptors at both the mRNA and protein level in lineage-negative, CD34(+), and CD133(+) cells than in NCs. Global gene expression analysis revealed considerably higher expression of genes associated with the production and secretion of proteins, migration, proliferation, and differentiation in lineage-negative cells than in CD34(+) or CD133(+) cell populations. Notably, after short-term incubation under serum-free conditions, lineage-negative cells and NCs produced significantly higher amounts of BDNF and NT-3 than under steady-state conditions. Finally, conditioned medium (CM) from lineage-negative SPCs exerted a beneficial impact on neural cell survival and proliferation. Collectively, our findings demonstrate that UCB-derived SPCs highly express NTs and their relevant receptors under steady-state conditions, NT expression is greater under stress-related conditions and that CM from SPCs favorable influence neural cell proliferation and survival. Understanding the mechanisms governing the characterization and humoral activity of subsets of SPCs may yield new therapeutic strategies that might be more effective in treating neurodegenerative disorders.
    PLoS ONE 12/2013; 8(12):e83833. DOI:10.1371/journal.pone.0083833 · 3.23 Impact Factor
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    • "It has been reported that subpopulations of MSCs with different properties do exist [64], [79]. Using different markers, some authors were able to select subpopulations of MSCs [80]. Furthermore, it has been shown that MSCs in the bone marrow have at least two developmental origins, one of them being the neural crest [81], [82]. "
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    ABSTRACT: Numerous strategies have been managed to improve functional recovery after spinal cord injury (SCI) but an optimal strategy doesn't exist yet. Actually, it is the complexity of the injured spinal cord pathophysiology that begets the multifactorial approaches assessed to favour tissue protection, axonal regrowth and functional recovery. In this context, it appears that mesenchymal stem cells (MSCs) could take an interesting part. The aim of this study is to graft MSCs after a spinal cord compression injury in adult rat to assess their effect on functional recovery and to highlight their mechanisms of action. We found that in intravenously grafted animals, MSCs induce, as early as 1 week after the graft, an improvement of their open field and grid navigation scores compared to control animals. At the histological analysis of their dissected spinal cord, no MSCs were found within the host despite their BrdU labelling performed before the graft, whatever the delay observed: 7, 14 or 21 days. However, a cytokine array performed on spinal cord extracts 3 days after MSC graft reveals a significant increase of NGF expression in the injured tissue. Also, a significant tissue sparing effect of MSC graft was observed. Finally, we also show that MSCs promote vascularisation, as the density of blood vessels within the lesioned area was higher in grafted rats. In conclusion, we bring here some new evidences that MSCs most likely act throughout their secretions and not via their own integration/differentiation within the host tissue.
    PLoS ONE 06/2012; 7(6):e39500. DOI:10.1371/journal.pone.0039500 · 3.23 Impact Factor
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