Mesenchymal stem cells for the sustained in vivo delivery of bioactive factors. Adv Drug Deliv Rev

Department of Internal Medicine, University of California, Davis, Sacramento, 95817, USA.
Advanced drug delivery reviews (Impact Factor: 15.04). 10/2010; 62(12):1167-74. DOI: 10.1016/j.addr.2010.09.013
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Mesenchymal stem cells (MSC) are a promising tool for cell therapy, either through direct contribution to the repair of bone, tendon and cartilage or as an adjunct therapy through protein production and immune mediation. They are an attractive vehicle for cellular therapies due to a variety of cell intrinsic and environmentally responsive properties. Following transplantation, MSC are capable of systemic migration, are not prone to tumor formation, and appear to tolerize the immune response across donor mismatch. These attributes combine to allow MSC to reside in many different tissue types without disrupting the local microenvironment and, in some cases, responding to the local environment with appropriate protein secretion. We describe work done by our group and others in using human MSC for the sustained in vivo production of supraphysiological levels of cytokines for the support of cotransplanted hematopoietic stem cells and enzymes that are deficient in animal models of lysosomal storage disorders such as MPSVII. In addition, the use of MSC engineered to secrete protein products has been reviewed in several fields of tissue injury repair, including but not limited to revascularization after myocardial infarction, regeneration of intervertebral disc defects and spine therapy, repair of stroke, therapy for epilepsy, skeletal tissue repair, chondrogenesis/knee and joint repair, and neurodegenerative diseases. Genetically engineered MSC have thus proven safe and efficacious in numerous animal models of disease modification and tissue repair and are poised to be tested in human clinical trials. The potential for these interesting cells to secrete endogenous or transgene products in a sustained and long-term manner is highly promising and is discussed in the current review.

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Available from: Jan A Nolta, Jul 03, 2015
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    • "Truly, it has been shown that transplantation of GM-MSCs which is expressing therapeutic growth factors generates new bone and cartilage formation much faster than exogenous treatment of growth factors (Lee et al. 2010). Thus, mesenchymal stem cells (MSCs) have received a great deal of attention as a delivery vehicle of growth factors following gene modification (Kofron and Laurencin 2006, Meyerrose et al. 2010, Porada and Almeida-Porada 2010, Qi et al. 2012) because they show sustained release of therapeutic growth factors as well as differentiation toward tissue specific cells at the same time. Therefore, these synergistic effects are able to distinctly enhance bone and cartilage tissue compared with individual treatment of MSCs and growth factors. "
    09/2014; 1(3):151-162. DOI:10.12989/bme.2014.1.3.151
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    • "MSCs have strong anti-inflammatory and immunosuppressive activity, rendering them very attractive for successful autologous, as well as heterologous, transplantations without requiring pharmacological immunosuppression [57, 58]. They do not give uncontrollable growth or tumour formation [59]. There is no need of genetic modification or pretreatment before transplantation; since MSCs are able to express in vivo immunosuppressive factors, immune rejection problems are overcame [60, 61]. "
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    ABSTRACT: Autism and autism spectrum disorders (ASDs) are complex neurodevelopmental disorders. ASDs are clinically defined by deficits in communication, social skills, and repetitive and/or restrictive interests and behaviours. With the prevalence rates for ASDs rapidly increasing, the need for effective therapies for autism is a priority for biomedical research. Currently available medications do not target the core symptoms, can have markedly adverse side-effects, and are mainly palliative for negative behaviours. The development of molecular and regenerative interventions is progressing rapidly, and medicine holds great expectations for stem cell therapies. Cells could be designed to target the observed molecular mechanisms of ASDs, that is, abnormal neurotransmitter regulation, activated microglia, mitochondrial dysfunction, blood-brain barrier disruptions, and chronic intestinal inflammation. Presently, the paracrine, secretome, and immunomodulatory effects of stem cells would appear to be the likely mechanisms of application for ASD therapeutics. This review will focus on the potential use of the various types of stem cells: embryonic, induced pluripotential, fetal, and adult stem cells as targets for ASD therapeutics.
    Stem cell International 10/2013; 2013(58–65):262438. DOI:10.1155/2013/262438 · 2.81 Impact Factor
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    • "Genetically modified stem cells have been proposed as a promising tool for cell therapy. They have been proven safe and effective in tissue repair or disease treatment by numerous animal tests and are now ready for human clinical trials.39 Our present data, together with those previously reported,9 support the notion that genetically engineered adipose stem cells with GDF5 might be applied for cartilage regeneration. "
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    ABSTRACT: Adipose-derived stem cells (ADSCs) are an attractive cell source for tissue engineering, and recently a modified aggregate culture of human ADSCs (hADSCs) was established based on preparation of three-dimensional (3D) cell aggregates in growth factor-enriched low serum medium using the hanging droplet method. Growth and differentiation factor 5 (GDF5) plays a critical role in chondrogenesis and cartilage development. In the present study, we examine (1) whether the modified aggregate culture is feasible for chondrogenic induction of hADSCs, (2) whether overexpressed GDF5 can promote chondrogenesis, and (3) the gene expression profile during chondrogenesis in this aggregate culture. hADSCs were infected with an adenovirus carrying the GDF5 gene (Ad-GDF5). Cells were cultured with chondrogenic media either in a modified aggregate culture or in an attached micromass culture that served as a control. The chondrogenic phenotype was assessed by morphology (n=8), biochemistry (n=3), and histology (n=2). Expression of 12 genes was determined by quantitative real-time polymerase chain reaction (n=3). We found that ADSCs cultured in the modified aggregates exhibited denser pellets and higher content of sulfated glycosaminoglycan (sGAG) compared with those cultured in the micromass. Infection of cells with Ad-GDF5 increased the aggregate size and sGAG content. It also up-regulated expression of GDF5, aggrecan, and leptin and down-regulated expression of COL I, while expression of COL II and COL 10 remained unchanged. We concluded that the modified aggregate culture is feasible for chondrogenic induction of human ADSCs. Infection with Ad-GDF5 appears to promote the chondrogenesis. These findings suggest that genetic modification of ADSCs with GDF5 in the modified aggregate culture could be useful for treating diseases with cartilage defects.
    08/2013; 2(4):258-65. DOI:10.1089/biores.2013.0014
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