216 Human Fat-Derived Mesenchymal Stem Cells Bioengineered to Secrete BMP4 Are Nononcogenic, Suppress Glioma, and Prolong Survival

Sara Ganaha, Rawan Al-Kharboosh, Alejandro Ruiz-Valls, Hugo Guerrero Cazares, Alfredo Quinones-Hinojosa

Research output: Contribution to journalArticle

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Abstract

INTRODUCTION: Glioblastoma is malignant, aggressive, and resistant to treatment. We demonstrate the ability of human adipose-derived mesenchymal stem cells (hAMSCs) to home to and suppress brain tumor initiating cells (BTIC) implicated in glioblastoma progression. Bone morphogenetic protein 4 (BMP4) has antitumor effects; however, a method to effectively deliver BMP4 to tumor sites still needs to be investigated. In this study, we investigated the use of hAMSCs as a vehicle to deliver BMP4 to BTICs, by using bioengineered BMP4-secreting hAMSCs (BMP4-hAMSC), for the treatment of glioblastoma.

METHODS: hAMSCs were transduced to express BMP4; effects on BTIC proliferation, differentiation, and migration were assessed with state-of-the-art proprietary nanotechnology developed by us. We investigated the effect of BTICs on hAMSC proliferation, differentiation, and malignant transformation into tumor-associated fibroblasts (TAFs) via Western blot, immunofluorescence, and real-time reverse transcriptase polymerase chain reaction. Nonobese diabetic/severe combined immunodeficiency mice were intracranially injected with BTICs derived from our own patient samples obtained from the operating room. Furthermore, mice underwent systemic injections of BMP4-hAMSCs to assess the safety of stem cell therapy, and their effect on glioblastoma proliferation and migration. Impact on survival was determined post-BMP4-hMSC treatment.

RESULTS: BMP4-hAMSCs decreased migration (P < .001), proliferation (P < .001), and induced differentiation (P < .001) of BTIC in vitro. In addition, hAMSCs remained multipotent upon exposure to BTIC-secreted factors, indicating retained stem cell characteristics and integrity. In addition, BMP4-hAMSCs did not undergo oncogenic transformation upon exposure to BTICs in vitro and in vivo. Moreover, systemically delivered BMP4-hAMSCs significantly improved median survival in mice, whereby they significantly outlived controls (P = .002).

CONCLUSION: BMP4-hAMSCs are nononcogenic and significantly decrease tumor burden and improve survival in mice. Our findings provide the groundwork for future clinical trials investigating the therapeutic potential of bioengineered stem cells for the treatment of glioblastoma.

Original languageEnglish (US)
Number of pages1
JournalNeurosurgery
Volume63
DOIs
StatePublished - Aug 1 2016

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Bone Morphogenetic Protein 4
Mesenchymal Stromal Cells
Glioma
Fats
Survival
Glioblastoma
Neoplastic Stem Cells
Brain Neoplasms
Stem Cells
Cell Movement
Cell Differentiation
Cell Proliferation
Therapeutics
Severe Combined Immunodeficiency
Nanotechnology
Operating Rooms
Cell- and Tissue-Based Therapy
Tumor Burden
Reverse Transcriptase Polymerase Chain Reaction
Fluorescent Antibody Technique

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

Cite this

216 Human Fat-Derived Mesenchymal Stem Cells Bioengineered to Secrete BMP4 Are Nononcogenic, Suppress Glioma, and Prolong Survival. / Ganaha, Sara; Al-Kharboosh, Rawan; Ruiz-Valls, Alejandro; Guerrero Cazares, Hugo; Quinones-Hinojosa, Alfredo.

In: Neurosurgery, Vol. 63, 01.08.2016.

Research output: Contribution to journalArticle

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abstract = "INTRODUCTION: Glioblastoma is malignant, aggressive, and resistant to treatment. We demonstrate the ability of human adipose-derived mesenchymal stem cells (hAMSCs) to home to and suppress brain tumor initiating cells (BTIC) implicated in glioblastoma progression. Bone morphogenetic protein 4 (BMP4) has antitumor effects; however, a method to effectively deliver BMP4 to tumor sites still needs to be investigated. In this study, we investigated the use of hAMSCs as a vehicle to deliver BMP4 to BTICs, by using bioengineered BMP4-secreting hAMSCs (BMP4-hAMSC), for the treatment of glioblastoma.METHODS: hAMSCs were transduced to express BMP4; effects on BTIC proliferation, differentiation, and migration were assessed with state-of-the-art proprietary nanotechnology developed by us. We investigated the effect of BTICs on hAMSC proliferation, differentiation, and malignant transformation into tumor-associated fibroblasts (TAFs) via Western blot, immunofluorescence, and real-time reverse transcriptase polymerase chain reaction. Nonobese diabetic/severe combined immunodeficiency mice were intracranially injected with BTICs derived from our own patient samples obtained from the operating room. Furthermore, mice underwent systemic injections of BMP4-hAMSCs to assess the safety of stem cell therapy, and their effect on glioblastoma proliferation and migration. Impact on survival was determined post-BMP4-hMSC treatment.RESULTS: BMP4-hAMSCs decreased migration (P < .001), proliferation (P < .001), and induced differentiation (P < .001) of BTIC in vitro. In addition, hAMSCs remained multipotent upon exposure to BTIC-secreted factors, indicating retained stem cell characteristics and integrity. In addition, BMP4-hAMSCs did not undergo oncogenic transformation upon exposure to BTICs in vitro and in vivo. Moreover, systemically delivered BMP4-hAMSCs significantly improved median survival in mice, whereby they significantly outlived controls (P = .002).CONCLUSION: BMP4-hAMSCs are nononcogenic and significantly decrease tumor burden and improve survival in mice. Our findings provide the groundwork for future clinical trials investigating the therapeutic potential of bioengineered stem cells for the treatment of glioblastoma.",
author = "Sara Ganaha and Rawan Al-Kharboosh and Alejandro Ruiz-Valls and {Guerrero Cazares}, Hugo and Alfredo Quinones-Hinojosa",
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T1 - 216 Human Fat-Derived Mesenchymal Stem Cells Bioengineered to Secrete BMP4 Are Nononcogenic, Suppress Glioma, and Prolong Survival

AU - Ganaha, Sara

AU - Al-Kharboosh, Rawan

AU - Ruiz-Valls, Alejandro

AU - Guerrero Cazares, Hugo

AU - Quinones-Hinojosa, Alfredo

PY - 2016/8/1

Y1 - 2016/8/1

N2 - INTRODUCTION: Glioblastoma is malignant, aggressive, and resistant to treatment. We demonstrate the ability of human adipose-derived mesenchymal stem cells (hAMSCs) to home to and suppress brain tumor initiating cells (BTIC) implicated in glioblastoma progression. Bone morphogenetic protein 4 (BMP4) has antitumor effects; however, a method to effectively deliver BMP4 to tumor sites still needs to be investigated. In this study, we investigated the use of hAMSCs as a vehicle to deliver BMP4 to BTICs, by using bioengineered BMP4-secreting hAMSCs (BMP4-hAMSC), for the treatment of glioblastoma.METHODS: hAMSCs were transduced to express BMP4; effects on BTIC proliferation, differentiation, and migration were assessed with state-of-the-art proprietary nanotechnology developed by us. We investigated the effect of BTICs on hAMSC proliferation, differentiation, and malignant transformation into tumor-associated fibroblasts (TAFs) via Western blot, immunofluorescence, and real-time reverse transcriptase polymerase chain reaction. Nonobese diabetic/severe combined immunodeficiency mice were intracranially injected with BTICs derived from our own patient samples obtained from the operating room. Furthermore, mice underwent systemic injections of BMP4-hAMSCs to assess the safety of stem cell therapy, and their effect on glioblastoma proliferation and migration. Impact on survival was determined post-BMP4-hMSC treatment.RESULTS: BMP4-hAMSCs decreased migration (P < .001), proliferation (P < .001), and induced differentiation (P < .001) of BTIC in vitro. In addition, hAMSCs remained multipotent upon exposure to BTIC-secreted factors, indicating retained stem cell characteristics and integrity. In addition, BMP4-hAMSCs did not undergo oncogenic transformation upon exposure to BTICs in vitro and in vivo. Moreover, systemically delivered BMP4-hAMSCs significantly improved median survival in mice, whereby they significantly outlived controls (P = .002).CONCLUSION: BMP4-hAMSCs are nononcogenic and significantly decrease tumor burden and improve survival in mice. Our findings provide the groundwork for future clinical trials investigating the therapeutic potential of bioengineered stem cells for the treatment of glioblastoma.

AB - INTRODUCTION: Glioblastoma is malignant, aggressive, and resistant to treatment. We demonstrate the ability of human adipose-derived mesenchymal stem cells (hAMSCs) to home to and suppress brain tumor initiating cells (BTIC) implicated in glioblastoma progression. Bone morphogenetic protein 4 (BMP4) has antitumor effects; however, a method to effectively deliver BMP4 to tumor sites still needs to be investigated. In this study, we investigated the use of hAMSCs as a vehicle to deliver BMP4 to BTICs, by using bioengineered BMP4-secreting hAMSCs (BMP4-hAMSC), for the treatment of glioblastoma.METHODS: hAMSCs were transduced to express BMP4; effects on BTIC proliferation, differentiation, and migration were assessed with state-of-the-art proprietary nanotechnology developed by us. We investigated the effect of BTICs on hAMSC proliferation, differentiation, and malignant transformation into tumor-associated fibroblasts (TAFs) via Western blot, immunofluorescence, and real-time reverse transcriptase polymerase chain reaction. Nonobese diabetic/severe combined immunodeficiency mice were intracranially injected with BTICs derived from our own patient samples obtained from the operating room. Furthermore, mice underwent systemic injections of BMP4-hAMSCs to assess the safety of stem cell therapy, and their effect on glioblastoma proliferation and migration. Impact on survival was determined post-BMP4-hMSC treatment.RESULTS: BMP4-hAMSCs decreased migration (P < .001), proliferation (P < .001), and induced differentiation (P < .001) of BTIC in vitro. In addition, hAMSCs remained multipotent upon exposure to BTIC-secreted factors, indicating retained stem cell characteristics and integrity. In addition, BMP4-hAMSCs did not undergo oncogenic transformation upon exposure to BTICs in vitro and in vivo. Moreover, systemically delivered BMP4-hAMSCs significantly improved median survival in mice, whereby they significantly outlived controls (P = .002).CONCLUSION: BMP4-hAMSCs are nononcogenic and significantly decrease tumor burden and improve survival in mice. Our findings provide the groundwork for future clinical trials investigating the therapeutic potential of bioengineered stem cells for the treatment of glioblastoma.

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