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Cited by 1123D Printing in Biomedical ResearchAcute Lymphoblastic Leukemia researchCellular Mechanics and Interactions

Three-Dimensional Microfluidic Tri-Culture Model of the Bone Marrow Microenvironment for Study of Acute Lymphoblastic Leukemia

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Bruce, Allison, Evans, Rebecca, Mezan, Ryan, Shi, Lin, Moses, Blake S., Martin, Karen H., Gibson, Laura F., Yang, Yong·2015·PLOS ONE
DOI 10.1371/journal.pone.0140506PMC PMC4619215
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Abstract

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.

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Authors
Bruce, A., Evans, R., Mezan, R., Shi, L., Moses, B. S., Martin, K. H., Gibson, L. F., & Yang, Y.
Affiliations
West Virginia University (US)
Corresponding author
  • Gibson, Laura F.
  • Yang, Yong
ORCID
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2015-10-21
Volume
10
Issue
10
Pages
e0140506
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0140506
PMC
PMC4619215
OpenAlex
W1857474768
Cited by
112
References
4
Citations by year
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FWCI
4.48
Type
journal article
Language
en
Update notices
correction (2015-12-30)
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • The Research Repository @ WVU (West Virginia University) (submittedVersion)
  • The Research Repository @ WVU (West Virginia University) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
National Institute of General Medical Sciences (P30GM103488, U54GM104942)
Topics
  • Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
Keywords
acute lymphoblastic leukemia, bone marrow microenvironment, mesenchymal stem cells, osteoblasts, collagen matrix, extracellular matrix stiffness, cell-cell interactions, cell-matrix interactions, cytarabine, chemoresistance, drug sensitivity, tumor cell survival
MeSH terms
Bone Marrow, Bone Marrow Cells, Cell Communication, Cell Survival, Humans, Osteoblasts, Coculture Techniques, Cell Culture Techniques, Microfluidics, Cell Line, Tumor, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Tumor Microenvironment, Mesenchymal Stem Cells

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