Abstract
Modifiable hydrogels have revealed tremendous insight into how physical characteristics of cells’ 3D environment drive stem cell lineage specification. However, in native tissues, cells do not passively receive signals from their niche. Instead they actively probe and modify their pericellular space to suit their needs, yet the dynamics of cells’ reciprocal interactions with their pericellular environment when encapsulated within hydrogels remains relatively unexplored. Here, we show that human bone marrow stromal cells (hMSC) encapsulated within hyaluronic acid-based hydrogels modify their surroundings by synthesizing, secreting and arranging proteins pericellularly or by degrading the hydrogel. hMSC’s interactions with this local environment have a role in regulating hMSC fate, with a secreted proteinaceous pericellular matrix associated with adipogenesis, and degradation with osteogenesis. Our observations suggest that hMSC participate in a bi-directional interplay between the properties of their 3D milieu and their own secreted pericellular matrix, and that this combination of interactions drives fate.
Highlights
Cells do not passively respond to signals delivered to them, whether they are static or dynamic
To study the role of cell-secreted extracellular matrix (ECM) in regulating human bone marrow stromal cells (hMSC) fate in 3D, we utilized hydrogels based on a well-described Michael addition between thiol-modified hyaluronic acid (HA) (S-HA) and poly(ethylene glycol) diacrylate (PEGDA) (Fig. 1a)[20]
As HA fragments of different molecular weights have been reported to influence human embryonic stem cell self-renewal/differentiation[37], we treated hMSC with fragments from degraded hydrogels, but observed no effects on gene expression (Supplementary Fig. 17). These findings suggest a bias in differentiation whereby cell-mediated formation of a proteinaceous pericellular matrix drives adipogenesis, and osteogenesis is driven by cell-mediated degradation of the matrix, which softens the hydrogel
Summary
Cells do not passively respond to signals delivered to them, whether they are static or dynamic. Many cell types actively modify their local environment by secreting a proteinaceous ECM and degrading their surroundings to suit their needs. This is apparent in the epidermis, where cell–ECM interactions reciprocally regulate the stem cell niche[14,15]. We show that when encapsulated within hyaluronic acid (HA)-based hydrogels, hMSC quickly modify their surroundings via protein secretion and/or matrix degradation. These cellmediated local modifications impact hMSC fate, with secretion of a proteinaceous pericellular matrix driving adipogenesis and degradation of the hydrogel matrix promoting osteogenesis. Our findings suggest that hydrogel physical properties may not direct fate in isolation, but rather impact how hMSC modulate their pericellular surroundings, which in turn directs differentiation
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