Three-Dimensional Microfluidic Tri-Culture Model of the Bone Marrow Microenvironment for Study of Acute Lymphoblastic Leukemia.
Acute lymphoblastic leukemia (ALL) initiates and progresses in the bone marrow, and as such, the marrow microenvironment is a critical regulatory component in development of this cancer. However, ALL studies were conducted mainly on flat plastic substrates, which do not recapitulate the characteristics of marrow microenvironments. To study ALL in a model of in vivo relevance, we have engineered a 3-D microfluidic cell culture platform. Biologically relevant populations of primary human bone marrow stromal cells, osteoblasts and human leukemic cells representative of an aggressive phenotype were encapsulated in 3-D collagen matrix as the minimal constituents and cultured in a microfluidic platform. The matrix stiffness and fluidic shear stress were controlled in a physiological range. The 3-D microfluidic as well as 3-D static models demonstrated coordinated cell-cell interactions between these cell types compared to the compaction of the 2-D static model. Tumor cell viability in response to an antimetabolite chemotherapeutic agent, cytarabine in tumor cells alone and tri-culture models for 2-D static, 3-D static and 3-D microfluidic models were compared. The present study showed decreased chemotherapeutic drug sensitivity of leukemic cells in 3-D tri-culture models from the 2-D models. The results indicate that the bone marrow microenvironment plays a protective role in tumor cell survival during drug treatment. The engineered 3-D microfluidic tri-culture model enables systematic investigation of effects of cell-cell and cell-matrix interactions on cancer progression and therapeutic intervention in a controllable manner, thus improving our limited comprehension of the role of microenvironmental signals in cancer biology.
Department of Chemical Engineering, West Virginia University, Morgantown, West Virginia, United States of America.
Allison
A
Bruce
Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia, United States of America.
Rebecca
R
Evans
Department of Chemical Engineering, West Virginia University, Morgantown, West Virginia, United States of America.
Ryan
R
Mezan
Department of Chemical Engineering, West Virginia University, Morgantown, West Virginia, United States of America.
Lin
L
Shi
Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia, United States of America.
Blake S
BS
Moses
Department of Neurobiology and Anatomy, West Virginia University, Morgantown, West Virginia, United States of America.
Karen H
KH
Martin
Alexander B. Osborn Hematopoietic Malignancy and Transplantation Program, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia, United States of America; Department of Microbiology, Immunology and Cell Biology, West Virginia University, Morgantown, West Virginia, United States of America.
Laura F
LF
Gibson
Department of Chemical Engineering, West Virginia University, Morgantown, West Virginia, United States of America.
Yong
Y
Yang
D001853:Bone Marrow / Q000473:pathology*; D001854:Bone Marrow Cells / Q000166:cytology; D002450:Cell Communication / Q000502:physiology; D018929:Cell Culture Techniques / Q000379:methods*; D045744:Cell Line, Tumor; D002470:Cell Survival; D018920:Coculture Techniques / Q000379:methods; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D044085:Microfluidics / Q000295:instrumentation / Q000379:methods*; D010006:Osteoblasts / Q000166:cytology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D059016:Tumor Microenvironment