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A small molecule modulator of prion protein enhances proliferation and engraftment of mesenchymal stem cells and extends their lifespan upon serial passage in culture

ABSTRACT: Human mesenchymal stem cells (hMSC) play an important role in the maintenance of bone and blood. Most protocols rely on their in vitro expansion prior to clinical use. However, several groups including our own have shown that hMSC lose proliferation and differentiation ability with serial passage in culture, limiting their clinical applications. Here we show that targeting prion protein (PrP) by chemical intervention delays this process. When PrP expression was knocked down, cultures showed significant reduction in proliferation and differentiation capacity. In contrast hMSC expanded in the presence of small molecule modulator of PrP expression, 3/689, showed extended lifespan up to 10 population doublings. Upon re-plating cultures contained more than double the number of clonogenic progenitors and showed a 10 fold increase in engraftment levels in bone marrow 5 weeks post-transplant. Human MSC treated with 3/689 showed enhanced protection from DNA damage and enhanced cell cycle progression. Gene expression profiling revealed upregulation of superoxide dismutase 2 in cells treated with 3/689, dependent on PrP expression, and suggests increased scavenging of reactive oxygen species as mechanism of action. These data point to PrP as a good target to delay loss of proliferation and differentiation of hMSC with expansion in culture.

ORGANISM(S): Homo sapiens

PROVIDER: GSE31205 | GEO | 2012/01/30

SECONDARY ACCESSION(S): PRJNA145989

REPOSITORIES: GEO

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A small molecule modulator of prion protein enhances proliferation and engraftment of mesenchymal stem cells and extends their lifespan upon serial passage in culture

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