Abstract
Key to realizing the diagnostic and therapeutic potential of human brown/brite adipocytes is the identification of a renewable, easily accessible and safe tissue source of progenitor cells, and an efficacious in vitro differentiation protocol. We show that macromolecular crowding (MMC) facilitates brown adipocyte differentiation in adult human bone marrow mesenchymal stem cells (bmMSCs), as evidenced by substantially upregulating uncoupling protein 1 (UCP1) and uncoupled respiration. Moreover, MMC also induced ‘browning’ in bmMSC-derived white adipocytes. Mechanistically, MMC creates a 3D extracellular matrix architecture enshrouding maturing adipocytes in a collagen IV cocoon that is engaged by paxillin-positive focal adhesions also at the apical side of cells, without contact to the stiff support structure. This leads to an enhanced matrix-cell signaling, reflected by increased phosphorylation of ATF2, a key transcription factor in UCP1 regulation. Thus, tuning the dimensionality of the microenvironment in vitro can unlock a strong brown potential dormant in bone marrow.
Highlights
Chest surgery or parental consent[15,16,17]
In the quest to establish a robust human cell model of brown and brite adipocyte physiology from an accessible and renewable cell source we have investigated the adipogenic potential of bone marrow derived mesenchymal stem cells
The differentiation efficacy in this cell model is comparable to other human cell models aiming at Brown adipocytes (BA) differentiation, including those based on induction of pluripotent cells[19,20], human multipotent adipose-derived stem cells isolated from young donors[17], and preadipocytes from the subclavicular region in human adults[15]
Summary
Chest surgery (mediastinum) or parental consent (prepubic fat pads in infants)[15,16,17] These anatomical locations preclude straightforward and repeatable access to BA progenitors. A robust protocol needs to be in place that facilitates the differentiation of human progenitors into BA efficaciously without genetic manipulation. Attempts have been made to employ substantial reprogramming of starting material, including iPS generation[19,20] We address here both issues demonstrating that bone marrow-derived mesenchymal stromal cells and the stromal vascular fraction of subcutaneous (SC) tissue of human adults contains progenitor cells with dormant thermogenic potential that can be unleashed with a specific differentiation protocol that makes use of a novel principle in tissue engineering, macromolecular crowding
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