Effects of Glucocorticoid Receptor Small Interfering RNA Delivered Using Poly Lactic-Co-Glycolic Acid Microparticles on Proliferation and Differentiation Capabilities of Human Mesenchymal Stromal Cells

Liu Hong; Na Wei; Vijaya Joshi; Yang Yu; NaJung Kim; Yogita Krishnamachari; Qiang Zhang; Aliasger K Salem

doi:10.1089/ten.tea.2011.0432

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Effects of Glucocorticoid Receptor Small Interfering RNA Delivered Using Poly Lactic-Co-Glycolic Acid Microparticles on Proliferation and Differentiation Capabilities of Human Mesenchymal Stromal Cells

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Effects of Glucocorticoid Receptor Small Interfering RNA Delivered Using Poly Lactic-Co-Glycolic Acid Microparticles on Proliferation and Differentiation Capabilities of Human Mesenchymal Stromal Cells

Liu Hong, Na Wei, Vijaya Joshi, Yang Yu, NaJung Kim, Yogita Krishnamachari, Qiang Zhang and Aliasger K Salem

Tissue engineering. Part A, Vol.18(7-8), pp.775-784

04/01/2012

DOI: 10.1089/ten.tea.2011.0432

PMCID: PMC3313605

PMID: 21988716

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Abstract

Bone marrow–derived mesenchymal stem cells (MSC) are a potential attractive source of cells for stem cell–based tissue regeneration, but the small number and reduced capabilities of MSC proliferation and differentiation due to in vitro replicative senescence and donor-associated pathophysiological factors, including age and estrogen depletion, severely restrict their potential usefulness in clinical applications. Glucocorticoids (GC) are well-known steroid hormones that regulate MSC proliferation and differentiation, but the defined effects and underlying mechanisms of endogenous glucocorticoids on MSC characteristics are not understood. This study investigated the effects of the blockage of endogenous GC using glucocorticoid receptor (GR) small interfering RNA (siRNA) delivered using biodegradable poly(lactic-co-glycolic acid) (PLGA) microparticles on proliferation and differentiation capabilities of human MSC in vitro . The results show that we can prepare PLGA microparticles as a delivery system for GR siRNA and maintain release of siRNA up to 40 days in vitro . Transfection of GR siRNA significantly downregulates GR and upregulates the expression of fibroblast growth factor-2 and Sox-11 of human MSC. MSC that have proliferated with endogenous GC blocked in vitro have greater proliferation rates and exhibit upregulated expression of osteogenic markers (alkaline phosphatase and core binding factor alpha 1) under differentiation stimulation after 1 week. Under adipogenic differentiation, MSC proliferated in vitro with siRNA transfection, resulting in significantly lower adipogenic markers (peroxisome proliferator-activated receptor and lipoprotein lipase) than controls. In conclusion, PLGA particles can serve as a tool for delivery of GR siRNA to effectively block the effects of endogenous GC on MSC, which has the potential to improve the capabilities of human MSC for clinical application by preventing replicative senescence.

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Title: Subtitle: Effects of Glucocorticoid Receptor Small Interfering RNA Delivered Using Poly Lactic-Co-Glycolic Acid Microparticles on Proliferation and Differentiation Capabilities of Human Mesenchymal Stromal Cells
Creators: Liu Hong - 1Dows Institute for Dental Research, College of Dentistry, University of Iowa, Iowa City, Iowa
Na Wei - 1Dows Institute for Dental Research, College of Dentistry, University of Iowa, Iowa City, Iowa
Vijaya Joshi - 2Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa
Yang Yu - 1Dows Institute for Dental Research, College of Dentistry, University of Iowa, Iowa City, Iowa
NaJung Kim - 3Department of Biomedical Engineering, College of Engineering, University of Iowa, Iowa City, Iowa
Yogita Krishnamachari - 2Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa
Qiang Zhang - 4Stomatology Health Care Center, Shenzhen Maternity and Child Healthcare Hospital, Shenzhen, China
Aliasger K Salem - 3Department of Biomedical Engineering, College of Engineering, University of Iowa, Iowa City, Iowa
Resource Type: Journal article
Publication Details: Tissue engineering. Part A, Vol.18(7-8), pp.775-784
DOI: 10.1089/ten.tea.2011.0432
PMID: 21988716
PMCID: PMC3313605
NLM abbreviation: Tissue Eng Part A
ISSN: 1937-3341
eISSN: 1937-335X
Publisher: Mary Ann Liebert, Inc
Language: English
Date published: 04/01/2012
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Pharmaceutical Sciences and Experimental Therapeutics; Prosthodontics; Craniofacial Anomalies Research Center; Dental Research; Chemical and Biochemical Engineering
Record Identifier: 9983985843402771

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