Mesenchymal stem cell-like properties of CD133+ glioblastoma initiating cells
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Lorena Favaro Pavon1,2, Tatiana Tais Sibov1, Daniela Mara de Oliveira3, Luciana C. Marti2,4, Francisco Romero Cabral2,5, Jean Gabriel de Souza6, Pamela Boufleur6, Suzana M.F. Malheiros1,7, Manuel A. de Paiva Neto1, Edgard Ferreira da Cruz8, Ana Marisa Chudzinski-Tavassi6, Sérgio Cavalheiro1
1Department of Neurology and Neurosurgery, Escola Paulista de Medicina-Universidade Federal de São Paulo (EPM-UNIFESP), São Paulo, Brazil
2Hospital Israelita Albert Einstein (HIAE), Experimental Research, São Paulo, Brazil
3Department of Genetics and Morphology, Universidade de Brasília, Brasília, Brazil
4Allergy and Immunopathology Graduate Program, Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, Brazil
5Faculdade de Ciências Médicas da São Casa de São Paulo, São Paulo, Brazil
6Biochemistry and Biophysics Laboratory, Butantan Institute, Neuro-Oncology Program, São Paulo, Brazil
7Hospital Israelita Albert Einstein (HIAE), Neuro-Oncology Program, São Paulo, Brazil
8Discipline of Nephrology, Escola Paulista de Medicina-Universidade Federal de São Paulo (EPM-UNIFESP), São Paulo, Brazil
Keywords: neurospheres, CD133+, MSC immunophenotype, TEM, tumorigenesis in vivo
Received: February 03, 2016 Accepted: April 16, 2016 Published: May 27, 2016
Glioblastoma is composed of dividing tumor cells, stromal cells and tumor initiating CD133+ cells. Recent reports have discussed the origin of the glioblastoma CD133+ cells and their function in the tumor microenvironment. The present work sought to investigate the multipotent and mesenchymal properties of primary highly purified human CD133+ glioblastoma-initiating cells. To accomplish this aim, we used the following approaches: i) generation of tumor subspheres of CD133+ selected cells from primary cell cultures of glioblastoma; ii) analysis of the expression of pluripotency stem cell markers and mesenchymal stem cell (MSC) markers in the CD133+ glioblastoma-initiating cells; iii) side-by-side ultrastructural characterization of the CD133+ glioblastoma cells, MSC and CD133+ hematopoietic stem cells isolated from human umbilical cord blood (UCB); iv) assessment of adipogenic differentiation of CD133+ glioblastoma cells to test their MSC-like in vitro differentiation ability; and v) use of an orthotopic glioblastoma xenograft model in the absence of immune suppression. We found that the CD133+ glioblastoma cells expressed both the pluripotency stem cell markers (Nanog, Mush-1 and SSEA-3) and MSC markers. In addition, the CD133+ cells were able to differentiate into adipocyte-like cells. Transmission electron microscopy (TEM) demonstrated that the CD133+ glioblastoma-initiating cells had ultrastructural features similar to those of undifferentiated MSCs. In addition, when administered in vivo to non-immunocompromised animals, the CD133+ cells were also able to mimic the phenotype of the original patient’s tumor. In summary, we showed that the CD133+ glioblastoma cells express molecular signatures of MSCs, neural stem cells and pluripotent stem cells, thus possibly enabling differentiation into both neural and mesodermal cell types.
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