Mesenchymal stem cells from human fat engineered to secrete BMP4 are nononcogenic, suppress brain cancer, and prolong survival.
OBJECTIVE
Glioblastoma is the most common adult primary malignant intracranial cancer. It is associated with poor outcomes because of its invasiveness and resistance to multimodal therapies. Human adipose-derived mesenchymal stem cells (hAMSC) are a potential treatment because of their tumor tropism, ease of isolation, and ability to be engineered. In addition, bone morphogenetic protein 4 (BMP4) has tumor-suppressive effects on glioblastoma and glioblastoma brain tumor-initiating cells (BTIC), but is difficult to deliver to brain tumors. We sought to engineer BMP4-secreting hAMSCs (hAMSCs-BMP4) and evaluate their therapeutic potential on glioblastoma.


METHODS
The reciprocal effects of hAMSCs on primary human BTIC proliferation, differentiation, and migration were evaluated in vitro. The safety of hAMSC use was evaluated in vivo by intracranial coinjections of hAMSCs and BTICs in nude mice. The therapeutic effects of hAMSCs and hAMSCs-BMP4 on the proliferation and migration of glioblastoma cells as well as the differentiation of BTICs, and survival of glioblastoma-bearing mice were evaluated by intracardiac injection of these cells into an in vivo intracranial glioblastoma murine model.


RESULTS
hAMSCs-BMP4 targeted both the glioblastoma tumor bulk and migratory glioblastoma cells, as well as induced differentiation of BTICs, decreased proliferation, and reduced the migratory capacity of glioblastomas in vitro and in vivo. In addition, hAMSCs-BMP4 significantly prolonged survival in a murine model of glioblastoma. We also demonstrate that the use of hAMSCs in vivo is safe.


CONCLUSIONS
Both unmodified and engineered hAMSCs are nononcogenic and effective against glioblastoma, and hAMSCs-BMP4 are a promising cell-based treatment option for glioblastoma.
Authors' Affiliations: Department of Neurosurgery and Oncology; Division of Pediatric Neurosurgery; Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health; Department of Biomedical Engineering, Johns Hopkins University School of Medicine; Department of Neurosurgery, University of Maryland, Baltimore, Maryland; Department of Biomedical Engineering, Yale University, New Haven, Connecticut; Department of Neurosurgery, Jefferson Medical College, Philadelphia, Pennsylvania; and Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
Qian
Q
Li
Olindi
O
Wijesekera
Sussan J
SJ
Salas
Joanna Y
JY
Wang
Mingxin
M
Zhu
Colette
C
Aprhys
Kaisorn L
KL
Chaichana
David A
DA
Chesler
Hao
H
Zhang
Christopher L
CL
Smith
Hugo
H
Guerrero-Cazares
Andre
A
Levchenko
Alfredo
A
Quinones-Hinojosa
D017667:Adipocytes / Q000166:cytology*; D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000096:biosynthesis* / Q000235:genetics; D001932:Brain Neoplasms / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D004195:Disease Models, Animal; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays
D055415:Bone Morphogenetic Protein 4