Non-hematopoietic stem cells as factories for in vivo therapeutic protein production

Sanz, Laura; Compte, Marta; Guijarro‐Muñoz, Irene; Álvarez‐Vallina, Luís

doi:10.1038/gt.2011.68

Cited by 16 publications

(11 citation statements)

References 74 publications

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“…Additionally, enhanced lung retention is achieved in a proinflammatory microenvironment [11]. Finally, MSCs can be gene enhanced for local production of therapeutically relevant transgenic paracrine factors [12]. Consequently, several studies have recently reported preventive and/or therapeutic benefit of unmodified or genetically engineered MSC transplantation in several acute and chronic airway pathologies [13][14][15].…”

mentioning

confidence: 99%

Human Mesenchymal Stem Cells Resolve Airway Inflammation, Hyperreactivity, and Histopathology in a Mouse Model of Occupational Asthma

Martínez-González

Cruz

Moreno

et al. 2014

Stem Cells and Development

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Occupational asthma (OA) is characterized by allergic airway inflammation and hyperresponsiveness, leading to progressive airway remodeling and a concomitant decline in lung function. The management of OA remains suboptimal in clinical practice. Thus, establishing effective therapies might overcome the natural history of the disease. We evaluated the ability of human adipose-tissue-derived mesenchymal stem cells (hASCs), either unmodified or engineered to secrete the IL-33 decoy receptor sST2, to attenuate the inflammatory and respiratory symptoms in a previously validated mouse model of OA to ammonium persulfate (AP). Twenty-four hours after a dermal AP sensitization and intranasal challenge regimen, the animals received intravenously 1 · 10 6 cells (either hASCs or hASCs overexpressing sST2) or saline and were analyzed at 1, 3, and 6 days after treatment. The infused hASCs induced an anti-inflammatory and restorative program upon reaching the APinjured, asthmatic lungs, leading to early reduction of neutrophilic inflammation and total IgE production, preserved alveolar architecture with nearly absent lymphoplasmacytic infiltrates, negligible smooth muscle hyperplasia/hypertrophy in the peribronchiolar areas, and baseline airway hyperreactivity (AHR) to methacholine. Local sST2 overexpression barely increased the substantial efficacy displayed by unmodified hASCs. Thus, hASCs may represent a viable multiaction therapeutic capable to adequately respond to the AP-injured lung environment by resolving inflammation, tissue remodeling, and bronchial hyperresponsiveness typical of OA.

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mentioning

confidence: 99%

Human Mesenchymal Stem Cells Resolve Airway Inflammation, Hyperreactivity, and Histopathology in a Mouse Model of Occupational Asthma

Martínez-González

Cruz

Moreno

et al. 2014

Stem Cells and Development

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“…The feasibility of in vivo secretion of full-length mAbs and engineered antibodies by different cell types has now been demonstrated using different techniques, such as genetic modification of ex vivo expanded terminally differentiated or precursor cells and in vivo gene transfer using viral vectors [20][21][22]. BsAbs have not remained on the margins of these gene therapy strategies, and several papers describing the in vivo secretion of bsAbs have been published (Table 1).…”

Section: In Vivo Secretion Of Fc-lacking Bispecific Antibodiesmentioning

confidence: 98%

In Vivo Secretion of Bispecific Antibodies Recruiting Lymphocytic Effector Cells

et al. 2013

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Engineered Fc-lacking bispecific antibodies have shown an exceptionally high potency for recruiting lymphocyte effector cells and enhancing antitumor activity, which is under evaluation in several clinical trials. However, current treatment regimens raise some issues that should be considered, such as the high cost of clinical-grade bispecific antibodies and the achievement of sustained therapeutic plasma levels. The use of gene transfer methods may circumvent problems related to large-scale production and purification, and result in sustained therapeutic plasma concentrations of the Fc-lacking bispecific antibodies. In fact, terminally differentiated cells and non-terminally differentiated cells can be genetically modified to secrete functionally active bispecific antibodies exerting clear anti-tumor effects. This review highlights the relevance of different promising strategies for in vivo delivery of therapeutic bispecific antibodies

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“…42 In conclusion, we find that nucleofection can be used to generate EPO-engineered MSCs, which secrete biologically active EPO in sufficient amounts to stimulate hematopoiesis in vivo. Future strategies aimed at the prevention of graft loss (for example, encapsulation of MSCs, exploitation of tissue tropism) 11,16,20 and inhibition of autoimmune responses are likely to extend the duration of action of this nonviral cell-based gene therapy where required.…”

Section: Nonviral Gene Transfer Into Murine Mscsmentioning

confidence: 99%

“…This includes their plasticity with differentiation potential into various types of mesodermal tissues, as well as their excellent targeting capabilities. [9][10][11] Besides the idea that MSCs naturally function to replace cells, they also appear to provide trophic support and exert immunomodulatory effects. 12 Importantly, MSCs express very low levels of major histocompatibility complex (MHC) molecules.…”

Section: Introductionmentioning

confidence: 99%

“…13 Therefore, MSCs have become one of the most popular cell types for in vivo therapeutic protein production. 11 A few recent studies have successfully used viral transfer of the epo gene into non-human primate, rodent and human MSCs for cell-based gene therapy. [14][15][16][17] Here, we wanted to establish nonviral techniques for MSC-based delivery of EPO.…”

Section: Introductionmentioning

confidence: 99%

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Nonviral gene delivery of erythropoietin by mesenchymal stromal cells

et al. 2011

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Erythropoietin (EPO) acts on erythroblasts in the bone marrow (BM) to stimulate the formation of red blood cells. In this study, we wanted to determine whether BM-derived mesenchymal stromal cells (MSCs) can be used as cellular vehicles to deliver EPO in mice without the use of viral vectors. After isolation and characterization of murine MSCs (mMSCs), different transient transfection procedures were compared for their efficacy of gene transfer of the pEGFP-N2 plasmid. Nucleofection outperformed magnetofection and lipofection. Stably transfected mMSCs were generated by selection with G418-disulfate and single-cellcolony-forming unit (sc-CFU) assays without changes in their proliferation capacity and osteogenic/adipogenic differentiation potential. Next, murine EPO was stably introduced into mMSCs by nucleofection of a plasmid encoding the epo and egfp genes. Intraperitoneal transplantation of EPO-expressing mMSCs increased serum EPO levels, hematocrit and hemoglobin of C57BL/6 mice within 1 week. The hematocrit remained elevated for 5 weeks, but production of antibodies against both transgenes was detected in the hosts and serum EPO levels normalized. Our results suggest that nonviral gene delivery into MSCs can be used to enhance the known beneficial effects MSCs by additional production of therapeutic factors like EPO in vivo.

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Non-hematopoietic stem cells as factories for in vivo therapeutic protein production

Cited by 16 publications

References 74 publications

Human Mesenchymal Stem Cells Resolve Airway Inflammation, Hyperreactivity, and Histopathology in a Mouse Model of Occupational Asthma

Human Mesenchymal Stem Cells Resolve Airway Inflammation, Hyperreactivity, and Histopathology in a Mouse Model of Occupational Asthma

In Vivo Secretion of Bispecific Antibodies Recruiting Lymphocytic Effector Cells

Nonviral gene delivery of erythropoietin by mesenchymal stromal cells

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