Skip to main content
  • Mesenchymal Stem Cells from Human Fat Can Be Engineered to Secrete BMP4, are Non-Oncogenic, and Suppress Glioblastoma Stem Cells

    Final Number:

    Kaisorn Chaichana MD; Qian Li; Olindi Wijesekera; Joanna Wang; Hugo Guerrero-Cazares; Andre Levchenko; Alfredo Quinones-Hinojosa MD

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2013 Annual Meeting

    Introduction: Glioblastoma(GB) is the most common adult primary intracranial cancer, and survival has not significantly changed recently. These tumors are thought to be maintained by a subpopulation of cells called glioma stem cells (GSCs). These cells are resistant to radiation and chemotherapy, making current treatment strategies ineffective. Human mesenchymal stem cells(hMSCs) have recently been found to exhibit brain tumor tropism, and proteins such as bone morphogenic protein 4 (BMP4) have been demonstrated to attenuate stem cells. Human adipose-derived MSCs(hAMSCs), a type of hMSCs, designed to secrete BMP4 may be a promising treatment option. This study aimed to evaluate the efficacy of engineered hAMSC-BMP4 in attenuating the migration and proliferation of GSCs, as well as evaluate the stability of these cells in the presence of GB in vitro and in vivo. These findings may eventually lead to a human clinical trial.

    Methods: hAMSCs were purchased and engineered to secrete BMP4 by a retroviral vector system. GSCs were derived from intraoperative human GB tissue. In vitro migration assays consisted of transwell and microfluidic chambers, while in vitro proliferation assays were done using MTS and EdU assays. An in vivo murine tumor model was used to evaluate proliferation and migration.

    Results: hAMSCs-BMP4 were able to induce differentiation, decrease proliferation, and reduce the migratory capacity of GSCs in vitro and in vivo. These cells were also able to target both the tumor bulk and migratory GB cells in vivo. Importantly, neither GB cells nor BMP4 modify hAMSC’s proliferation and differentiation.

    Conclusions: This study demonstrates the potential efficacy of hAMSCs-BMP4 for GB treatment. These engineered cells are able to deliver anticancer proteins to both the tumor bulk and satellite cells. They are not changed by GB cells. These findings may potentially lead to human clinical trials.

    Patient Care: Glioblastoma (GB) is the most common adult primary intracranial cancer, and survival has not significantly changed recently. We have developed a new way to treat patients with this disease that may improve outcomes.

    Learning Objectives: To identify the role that mesenchymal stem cells that are engineered to secrete BMP4 have to glioblastoma stem cells.

    References: 1. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, et al: Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756-760, 2006 2. Chaichana KL, Guerrero-Cazares H, Capilla-Gonzalez V, Zamora-Berridi G, Achanta P, Gonzalez-Perez O, et al: Intra-operatively obtained human tissue: protocols and techniques for the study of neural stem cells. Journal of neuroscience methods 180:116-125, 2009 3. Garzon-Muvdi T, Schiapparelli P, ap Rhys C, Guerrero-Cazares H, Smith C, Kim DH, et al: Regulation of brain tumor dispersal by NKCC1 through a novel role in focal adhesion regulation. PLoS Biol 10:e1001320, 2012 4. Kang Y: Analysis of cancer stem cell metastasis in xenograft animal models. Methods Mol Biol 568:7-19, 2009 5. Kim DH, Lipke EA, Kim P, Cheong R, Thompson S, Delannoy M, et al: Nanoscale cues regulate the structure and function of macroscopic cardiac tissue constructs. Proc Natl Acad Sci U S A 107:565-570, 2010 6. Peng H, Chen ST, Wergedal JE, Polo JM, Yee JK, Lau KH, et al: Development of an MFG-based retroviral vector system for secretion of high levels of functionally active human BMP4. Mol Ther 4:95-104, 2001 7. Piccirillo SG, Reynolds BA, Zanetti N, Lamorte G, Binda E, Broggi G, et al: Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 444:761-765, 2006 8. Quinones-Hinojosa A, Chaichana K: The human subventricular zone: a source of new cells and a potential source of brain tumors. Exp Neurol 205:313-324, 2007 9. Quinones-Hinojosa A, Chaichana K: The human subventricular zone: a source of new cells and a potential source of brain tumors. Experimental neurology 205:313-324, 2007 10. Strioga M, Viswanathan S, Darinskas A, Slaby O, Michalek J: Same or not the same? Comparison of adipose tissue-derived versus bone marrow-derived mesenchymal stem and stromal cells. Stem Cells Dev 21:2724-2752, 2012 11. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987-996, 2005 12. Tait MJ, Petrik V, Loosemore A, Bell BA, Papadopoulos MC: Survival of patients with glioblastoma multiforme has not improved between 1993 and 2004: analysis of 625 cases. British journal of neurosurgery 21:496-500, 2007

We use cookies to improve the performance of our site, to analyze the traffic to our site, and to personalize your experience of the site. You can control cookies through your browser settings. Please find more information on the cookies used on our site. Privacy Policy