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Previous work demonstrated an accelerated in vitro and in vivo wound healing response when insulinoma cells were used to deliver insulin to scratches in keratinocyte mono- layers and chronic diabetic excise wounds in mice, respectively. When combined with mesenchymal stem cells (MSCs), the response was amplified (healing in 14 vs. 35+ days). To isolate the role of insulin in the response and exclude any potential contribution of an un known cancer moiety released by the insulinoma cells, the effect on wound healing of multiple lines derived from the same insulinoma was examined.
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Validating Hydrogel Microencapsulated Insulin Secreting Cells for Wound Healing
Previous work demonstrated an accelerated in vitro and in vivo wound healing response when insulinoma cells were used to deliver insulin to scratches in keratinocyte mono- layers and chronic diabetic excise wounds in mice, respectively. When combined with mesenchymal stem cells (MSCs), the response was amplified (healing in 14 vs. 35+ days). To isolate the role of insulin in the response and exclude any potential contribution of an unknown cancer moiety released by the insulinoma cells, the effect on wound healing of multiple lines derived from the same insulinoma was examined.
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- Award ID(s):
- 1752079
- PAR ID:
- 10138989
- Date Published:
- Journal Name:
- Northeast Bioengineering Conference
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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We previously demonstrated that insulin secreting cells (ISCs) accelerate healing of chronic wounds, and it is known that mesenchymal stem cells (MSCs) also accelerate wound healing. Here, we report that the combination of both cell types coencapsulated into a synthetic hydrogel dressing accelerates chronic wound healing 3x faster than control and 2x faster than each cell type delivered singly. Specifically, insulin released by ISCs activates the PI3/Akt pathway, which is vital to the function and survival of MSCs. MSCs in turn improve the viability and function of ISCs.more » « less
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Abstract Background Wound healing is one of the defining features of life and is seen not only in tissues but also within individual cells. Understanding wound response at the single-cell level is critical for determining fundamental cellular functions needed for cell repair and survival. This understanding could also enable the engineering of single-cell wound repair strategies in emerging synthetic cell research. One approach is to examine and adapt self-repair mechanisms from a living system that already demonstrates robust capacity to heal from large wounds. Towards this end, Stentor coeruleus , a single-celled free-living ciliate protozoan, is a unique model because of its robust wound healing capacity. This capacity allows one to perturb the wounding conditions and measure their effect on the repair process without immediately causing cell death, thereby providing a robust platform for probing the self-repair mechanism. Results Here we used a microfluidic guillotine and a fluorescence-based assay to probe the timescales of wound repair and of mechanical modes of wound response in Stentor . We found that Stentor requires ~ 100–1000 s to close bisection wounds, depending on the severity of the wound. This corresponds to a healing rate of ~ 8–80 μm 2 /s, faster than most other single cells reported in the literature. Further, we characterized three distinct mechanical modes of wound response in Stentor : contraction, cytoplasm retrieval, and twisting/pulling. Using chemical perturbations, active cilia were found to be important for only the twisting/pulling mode. Contraction of myonemes, a major contractile fiber in Stentor , was surprisingly not important for the contraction mode and was of low importance for the others. Conclusions While events local to the wound site have been the focus of many single-cell wound repair studies, our results suggest that large-scale mechanical behaviors may be of greater importance to single-cell wound repair than previously thought. The work here advances our understanding of the wound response in Stentor and will lay the foundation for further investigations into the underlying components and molecular mechanisms involved.more » « less
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Wound healing is a multivariate process involving the coordinated response of numerous proteins and cell types. Accordingly, biomedical research has seen an increased adoption of the use of in vitro wound healing assays with complexity beyond that offered by traditional well-plate constructs. These microphysiological systems (MPS) seek to recapitulate one or more physiological features of the in vivo microenvironment, while retaining the analytical capacity of more reductionist assays. Design efforts to achieve relevant wound healing physiology include the use of dynamic perfusion over static culture, the incorporation of multiple cell types, the arrangement of cells in three dimensions, the addition of biomechanically and biochemically relevant hydrogels, and combinations thereof. This review provides a brief overview of the wound healing process and in vivo assays, and we critically review the current state of MPS and supporting technologies for modelling and studying wound healing. We distinguish between MPS that seek to inform a particular phase of wound healing, and constructs that have the potential to inform multiple phases of wound healing. This distinction is a product of whether analysis of a particular process is prioritized, or a particular physiology is prioritized, during design. Material selection is emphasized throughout, and relevant fabrication techniques discussed.more » « less
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Abstract Epithelial wound healing involves the collective responses of many cells, including those at the wound margin (marginal cells) and those that lack direct contact with the wound (submarginal cells). How these responses are induced and coordinated to produce rapid, efficient wound healing remains poorly understood. Extracellular ATP (eATP) is implicated as a signal in epithelial wound healing in vertebrates. However, the role of eATP in wound healing in vivo and the cellular responses to eATP are unclear. Almost nothing is known about eATP signaling in non-bilaterian metazoans (Cnidaria, Ctenophora, Placozoa,andPorifera). Here, we show that eATP promotes closure of epithelial wounds in vivo in the cnidarianClytia hemisphaerica(Clytia) indicating that eATP signaling is an evolutionarily ancient strategy in wound healing. Furthermore, eATP increases F-actin accumulation at the edges of submarginal cells. In Clytia, this indicates eATP is involved in coordinating cellular responses during wound healing, acting in part by promoting actin remodeling in cells at a distance from the wound. We also present evidence that eATP activates a cation channel in Clytia epithelial cells. This implies that the eATP signal is transduced through a P2X receptor (P2XR). Phylogenetic analyses identified four Clytia P2XR homologs and revealed two deeply divergent major branches in P2XR evolution, necessitating revision of current models. Interestingly, simple organisms such as cellular slime mold appear exclusively on one branch, bilaterians are found exclusively on the other, and many non-bilaterian metazoans, including Clytia, have P2XR sequences from both branches. Together, these results re-draw the P2XR evolutionary tree, provide new insights into the origin of eATP signaling in wound healing, and demonstrate that the cytoskeleton of submarginal cells is a target of eATP signaling.more » « less
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