Notch‐inducing hydrogels reveal a perivascular switch of mesenchymal stem cell fate

Abstract

The fate of mesenchymal stem cells (MSCs) in the perivascular niche, as well as factors controlling their fate, is poorly understood. Here, we study MSCs in the perivascular microenvironment of endothelial capillaries by modifying a synthetic 3D biomimetic poly(ethylene glycol) (PEG)-hydrogel system We show that MSCs together with endothelial cells form micro-capillary networks specifically in soft PEG hydrogels. Transcriptome analysis of human MSCs isolated from engineered capillaries shows a prominent switch in extracellular matrix (ECM) production. We demonstrate that the ECM phenotypic switch of MSCs can be recapitulated in the absence of endothelial cells by functionalizing PEG hydrogels with the Notch-activator Jagged1. Moreover, transient culture of MSCs in Notch-inducing microenvironments reveals the reversibility of this ECM switch. These findings provide insight into the perivascular commitment of MSCs by use of engineered niche-mimicking synthetic hydrogels.

Deciphering the relative roles of matrix metalloproteinase‐ and plasmin‐mediated matrix degradation during capillary morphogenesis using engineered hydrogels

“…These findings are also consistent with other studies noting that increasing crosslink degradability or a more loosely crosslinked network structure correlate with increased capillary morphogenesis. Furthermore, in adipocyte‐derived stem cell‐EC cocultures, others have observed evidence that plasmin‐mediated ECM degradation becomes increasingly important in densely crosslinked fibrin .…”

“…Our model also provides a tool to investigate matrix remodeling in organotypic capillary morphogenesis with specific EC and stromal cell combinations. Finally, the unique matrix‐centric perspective of these studies provides strong evidence to justify the preferential selection of MMP‐degradable peptide crosslinkers in synthetic hydrogels used to study vascular morphogenesis and promote vascularization.…”

Harnessing the secreted extracellular matrix to engineer tissues

“…However, cells encapsulated within hydrogels can quickly remodel their surroundings by assembling secreted proteins around themselves [4][5][6] . Although it has long been known that cells secrete proteins pericellularly, it is now clear that local cell-mediated modifications can quickly override the physical and biological cues presented by the hydrogel.…”

“…However, this is now changing. It has been recently shown that, when encapsulated within hydrogels, human bonemarrow-derived MSCs (hMSCs) quickly modify their surroundings by secreting and assembling proteins around themselves [4][5][6] (Fig. 1).…”

“…The secreted matrix can be detected around cells as soon as 4 hours after encapsulation 5,6 . Although cells quickly engage with the secreted matrix (blocking integrin-mediated interactions with soluble peptides results in reduced cell viability 4 ), the secreted matrix does not make integrin-mediated interactions with the hydrogel entirely dispensable, as hMSCs within inert hydrogels lacking adhesive motifs show reduced viability 25 .…”