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Chemoresistance is a significant problem in the effective treatment of bone metastasis. Adipocytes are a major stromal cell type in the bone marrow and may play a crucial role in developing microenvironment-driven chemoresistance. However, detailed investigation remains challenging due to the anatomical inaccessibility and intrinsic tissue complexity of the bone marrow microenvironment. In this study, we developed 2D and 3D in vitro models of bone marrow adipocytes to examine the mechanisms underlying adipocyte-induced chemoresistance. We first established a protocol for the rapid and robust differentiation of human bone marrow stromal cells (hBMSCs) into mature adipocytes in 2D tissue culture plastic using rosiglitazone (10 μM), a PPARγ agonist. Next, we created a 3D adipocyte culture model by inducing aggregation of hBMSCs and adipogenesis to create adipocyte spheroids in porous hydrogel scaffolds that mimic bone marrow sinusoids. Simulated chemotherapy treatment with doxorubicin (2.5 μM) demonstrated that mature adipocytes sequester doxorubicin in lipid droplets, resulting in reduced cytotoxicity. Lastly, we performed direct coculture of human multiple myeloma cells (MM1.S) with the established 3D adipocyte model in the presence of doxorubicin. This resulted in significantly accelerated multiple myeloma proliferation following doxorubicin treatment. Our findings suggest that the sequestration of hydrophobic chemotherapeutics by mature adipocytes represents a potent mechanism of bone marrow microenvironment-driven chemoresistance.
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This content will become publicly available on May 6, 2026
Involvement of long non-coding RNA (lncRNA) MALAT1 in shear stress regulated adipocyte differentiation
Adipocyte differentiation plays an important role in bone remodeling due to secretory factors that can directly modulate osteoblast and osteoclast, thus affecting overall bone mass and skeletal integrity. Excessive adipocyte differentiation within the bone marrow microenvironment can lead to decreased bone mass, eventually causing osteoporosis. The mechanical microenvironment of bone marrow, including fluid shear, maintains the balance of adipocyte and osteoblast differentiation during bone remodeling. However, how mechanical cues interact with long noncoding RNA (lncRNA) and regulate adipocyte differentiation remains unexplored. In this study, we investigated the mechanosensitive role of lncRNA MALAT1 during mesenchymal stem cells (MSCs) adipocyte differentiation. By applying physiologically relevant shear stress, MSCs experienced morphological changes and adipocyte differentiation differences. Shear stress inhibits adipocyte differentiation of MSCs, demonstrated by reduced oil-red-o-stained lipid droplets. Silencing MALAT1 also results in reduced adipocyte differentiation. By leveraging a novel gapmer double stranded locked nuclei acid nanobiosensor, we showed that shear stress inhibits MALAT1 expression, with significantly reduced fluorescence intensity. Our findings indicate that shear stress influences adipocyte differentiation mainly through the downregulation of MALAT1, highlighting a significant interplay between biophysical cues and lncRNAs. This interaction is crucial for understanding the complexities of bone remodeling and the potential therapeutic targeting of lncRNAs to treat bone-related disorders.
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- Award ID(s):
- 1847019
- PAR ID:
- 10636068
- Publisher / Repository:
- Frontier Media
- Date Published:
- Journal Name:
- Frontiers in Bioengineering and Biotechnology
- Volume:
- 13
- ISSN:
- 2296-4185
- Subject(s) / Keyword(s):
- shear stress adipocyte differentiation osteogenic differentiation long non-coding RNA lncRNA MALAT1 nanobiosensor
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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