Transcriptional profiling of interleukin-2-primed human adipose derived mesenchymal stem cells revealed dramatic changes in stem cells response imposed by replicative senescence

// Ping Niu 1,* , Aibek Smagul 2,* , Lu Wang 3 , Aiman Sadvakas 2 , Ying Sha 3 , Laura M. Perez 4 , Aliya Nussupbekova 2 , Aday Amirbekov 2 , Akan A. Akanov 2 , Beatriz G. Galvez 4 , I. King Jordan 3,5 and Victoria V. Lunyak 6 1 Department of Pediatrics, Renmin Hospital of Wuhan University, Wuhan, China 2 S.D. Asfendiyarov Kazakh National Medical University, Almaty, Kazakhstan 3 School of Biology, Georgia Institute of Technology, Atlanta, GA 4 Cardiac Development and Repair Department, National Center for Cardiovascular Research (CNIC), Madrid, Spain 5 PanAmerican Bioinformatics Institute, Santa Marta, Magdalena, Colombia 6 Aelan Cell Technologies, Inc, San Francisco, CA * These authors have contributed equally to this work Correspondence to: Victoria V. Lunyak, email: // Keywords : mesenchymal stem cells, IL-2, aging, cancer, immunomodulation Received : April 17, 2015 Accepted : June 11, 2015 Published : July 14, 2015 Abstract Inflammation is a double-edged sword with both detrimental and beneficial consequences. Understanding of the mechanisms of crosstalk between the inflammatory milieu and human adult mesenchymal stem cells is an important basis for clinical efforts. Here, we investigate changes in the transcriptional response of human adipose-derived stem cells to physiologically relevant levels of IL-2 (IL-2 priming) upon replicative senescence. Our data suggest that replicative senescence might dramatically impede human mesenchymal stem cell (MSC) function via global transcriptional deregulation in response to IL-2. We uncovered a novel senescence-associated transcriptional signature in human adipose-derived MSCs hADSCs after exposure to pro-inflammatory environment: significant enhancement of the expression of the genes encoding potent growth factors and cytokines with anti-inflammatory and migration-promoting properties, as well as genes encoding angiogenic and anti-apoptotic promoting factors, all of which could participate in the establishment of a unique microenvironment. We observed transcriptional up-regulation of critical components of the nitric oxide synthase pathway (iNOS) in hADSCs upon replicative senescence suggesting, that senescent stem cells can acquire metastasis-promoting properties via stem cell-mediated immunosuppression. Our study highlights the importance of age as a factor when designing cell-based or pharmacological therapies for older patients and predicts measurable biomarkers characteristic of an environment that is conducive to cancer cells invasiveness and metastasis.