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Bone morphogenic protein 2 is a key regulator of spheroidal aggregates of mesenchymal stem cells
Author(s) -
Tamama Kenichi,
Funnell Jessica,
Cesarz Zoe
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.695.2
Subject(s) - mesenchymal stem cell , spheroid , microbiology and biotechnology , bone morphogenetic protein 2 , signal transduction , cell signaling , chemistry , bone morphogenetic protein , biology , cell culture , gene , genetics , biochemistry , in vitro
Cell therapy with adult mesenchymal stem cells (MSCs) is a promising approach in regenerative medicine and autoimmune disease. There are various approaches to improve the efficacy of MSC‐based therapeutics, and MSC preparation as spheroidal aggregates or MSC spheroids is a novel preparatory and delivery method. Spheroid formation induces a dramatic change in the gene expression profile of MSCs. Self‐activation of interleukin‐1 (IL1) signaling was shown to be upstream of both pro‐ and anti‐inflammatory genes in MSC spheroids, but the molecular pathways that initiate IL1 signaling remain unknown. As BMP2 up‐regulation precedes that of IL1B expression during spheroid formation, we hypothesized that BMP2 signaling triggers IL1 signaling in MSC spheroids. Contrary to expectations, BMP2 signaling decreased expression of IL1B and downstream genes in a SMAD6‐dependent manner. Conversely, IL1B signaling enhanced BMP2 expression. Another major difference between 2D monolayer culture and 3D spheroid culture is the Young's elasticity modulus, or stiffness, of the materials surrounding the cells, as there is a million‐fold difference between a plastic surface for standard 2D culture (GPa) and 3D spheroidal aggregate (0.1 kPa). We tested another hypothesis that soft elasticity‐associated mechano‐signaling functions as a regulatory mechanism in the early phase of spheroid formation. Both BMP2 expression and inflammatory signaling are up‐regulated in an elasticity‐associated signaling dependent manner in MSCs. Finally, BMP2 signaling enhanced cell survival and cell spreading of MSC spheroids. In summary, our study suggests that BMP2 is a key regulator of MSC spheroids. Support or Funding Information This study was supported by University of Pittsburgh Schools of Health Sciences (Bridge Funding Category One), University Pittsburgh Medical Center Health System (Competitive Medical Research Fund), and departmental funds (Department of Pathology, University of Pittsburgh School of Medicine)(to KT) and University of Pittsburgh School of Medicine Summer Undergraduate Research Program (SURP) (to JF).