Cell Chirality of Micropatterned Endometrial Microvascular Endothelial Cells.

Chirality is an intrinsic cellular property that describes cell polarization biases along the left-right axis, apicobasal axis, or front-rear axes. Cell chirality plays a significant role in the arrangement of organs in the body as well as in the orientation of organelles, cytoskeletons, and cells. Vascular networks within the endometrium, the mucosal inner lining of the uterus, commonly display spiral architectures that rapidly form across the menstrual cycle. Herein, the role of endometrial-relevant extracellular matrix stiffness, composition, and soluble signals on endometrial endothelial cell chirality is systematically examined using a high-throughput microarray. Endometrial endothelial cells display marked patterns of chirality as individual cells and as cohorts in response to substrate stiffness and environmental cues. Vascular networks formed from endometrial endothelial cells also display shifts in chirality as a function of exogenous hormones. Changes in cellular-scale chirality correlate with changes in vascular network parameters, suggesting a critical role for cellular chirality in directing endometrial vessel network organization.

Host type 2 immune response to xenogeneic serum components impairs biomaterial-directed osteo-regenerative therapies.

The transformative potential of cells as therapeutic agents is being realized in a wide range of applications, from regenerative medicine to cancer therapy to autoimmune disorders. The majority of these therapies require ex vivo expansion of the cellular product, often utilizing fetal bovine serum (FBS) in the culture media. However, the impact of residual FBS on immune responses to cell therapies and the resulting cell therapy outcomes remains unclear. Here, we show that hydrogel-delivered FBS elicits a robust type 2 immune response characterized by infiltration of eosinophils and CD4+ T cells. Host secretion of cytokines associated with type 2 immunity, including IL-4, IL-5, and IL-13, is also increased in FBS-containing hydrogels. We demonstrate that the immune response to xenogeneic serum components dominates the local environment and masks the immunomodulatory effects of biomaterial-delivered mesenchymal stromal/stem cells. Importantly, delivery of relatively small amounts of FBS (3.2% by volume) within BMP-2-containing biomaterial constructs dramatically reduces the ability of these constructs to promote de novo bone formation in a radial defect model in immunocompetent mice. These results urge caution when interpreting the immunological and tissue repair outcomes in immunocompetent pre-clinical models from cells and biomaterial constructs that have come in contact with xenogeneic serum components.

Integrin-specific hydrogels modulate transplanted human bone marrow-derived mesenchymal stem cell survival, engraftment, and reparative activities.

Stem cell therapies are limited by poor cell survival and engraftment. A hurdle to the use of materials for cell delivery is the lack of understanding of material properties that govern transplanted stem cell functionality. Here, we show that synthetic hydrogels presenting integrin-specific peptides enhance the survival, persistence, and osteo-reparative functions of human bone marrow-derived mesenchymal stem cells (hMSCs) transplanted in murine bone defects. Integrin-specific hydrogels regulate hMSC adhesion, paracrine signaling, and osteoblastic differentiation in vitro. Hydrogels presenting GFOGER, a peptide targeting α2ß1 integrin, prolong hMSC survival and engraftment in a segmental bone defect and result in improved bone repair compared to other peptides. Integrin-specific hydrogels have diverse pleiotropic effects on hMSC reparative activities, modulating in vitro cytokine secretion and in vivo gene expression for effectors associated with inflammation, vascularization, and bone formation. These results demonstrate that integrin-specific hydrogels improve tissue healing by directing hMSC survival, engraftment, and reparative activities.