“…In vivo , a feature of stable microvessels is the presence of pericytes that wrap around the vessels and promote a mature phenotype. As we have noted before (24; 29) a proportion of the stromal cells we add can differentiate into pericytes, and we see that also in the islet-VMO (Fig. 1D-E).…”
Insulin is an essential regulator of blood glucose homeostasis that is produced exclusively by β cells within the pancreatic islets of healthy individuals. In those affected by diabetes, immune inflammation, damage, and destruction of islet β cells leads to insulin deficiency and hyperglycemia. Current efforts to understand the mechanisms underlying β cell damage in diabetes rely on in vitro-cultured cadaveric islets. However, isolation of these islets involves removal of crucial matrix and vasculature that supports islets in the intact pancreas. Unsurprisingly, these islets demonstrate reduced functionality over time in standard culture conditions, thereby limiting their value for understanding native islet biology. Leveraging a novel, vascularized micro-organ (VMO) approach, we have recapitulated elements of the native pancreas by incorporating isolated human islets within a three-dimensional matrix nourished by living, perfusable blood vessels. Importantly, these islets show long-term viability and maintain robust glucose-stimulated insulin responses. Furthermore, vessel-mediated delivery of immune cells to these tissues provides a model to assess islet-immune cell interactions and subsequent islet killing -- key steps in type 1 diabetes pathogenesis. Together, these results establish the islet-VMO as a novel, ex vivo platform for studying human islet biology in both health and disease.
“…In vivo , a feature of stable microvessels is the presence of pericytes that wrap around the vessels and promote a mature phenotype. As we have noted before (24; 29) a proportion of the stromal cells we add can differentiate into pericytes, and we see that also in the islet-VMO (Fig. 1D-E).…”
Insulin is an essential regulator of blood glucose homeostasis that is produced exclusively by β cells within the pancreatic islets of healthy individuals. In those affected by diabetes, immune inflammation, damage, and destruction of islet β cells leads to insulin deficiency and hyperglycemia. Current efforts to understand the mechanisms underlying β cell damage in diabetes rely on in vitro-cultured cadaveric islets. However, isolation of these islets involves removal of crucial matrix and vasculature that supports islets in the intact pancreas. Unsurprisingly, these islets demonstrate reduced functionality over time in standard culture conditions, thereby limiting their value for understanding native islet biology. Leveraging a novel, vascularized micro-organ (VMO) approach, we have recapitulated elements of the native pancreas by incorporating isolated human islets within a three-dimensional matrix nourished by living, perfusable blood vessels. Importantly, these islets show long-term viability and maintain robust glucose-stimulated insulin responses. Furthermore, vessel-mediated delivery of immune cells to these tissues provides a model to assess islet-immune cell interactions and subsequent islet killing -- key steps in type 1 diabetes pathogenesis. Together, these results establish the islet-VMO as a novel, ex vivo platform for studying human islet biology in both health and disease.
“…The percentage of E-cadherin+, E-cadherin+ and vimentin+, and vimentin + HCT116 cells increased on-chip, while the percentage of cells that were negative for both E-cadherin and vimentin decreased on-chip as compared to HCT116 cultured on plastic. Taken together, these results suggest that HCT116 tumor cells are more heterogeneous on-chip, recently corroborated by another tumor-on-a-chip model system ( Hachey et al., 2021 ). Figure 4 CRC cell heterogeneity during intravasation on-chip (A) Representative images depict the phenotypic heterogeneity of invaded HCT116 cells adhered to endothelial cells in the bottom chip channel.…”
A human colorectal cancer chip recapitulates aspects of CRC biology On-chip imaging and metabolomic effluent analyses offer insight into progression Organ-on-chip conditions induce phenotypic heterogeneity compared to 2D cultures Stromal cell cross talk and mechanical forces increase tumor cell intravasation
“…Standardization is easier, having a lot of replicates of the immune-tumor cell interaction, when NK cells are faced with a spheroid of a defined size. Indeed, standardization is a key point to translate in vitro data to the clinic [ 155 , 156 , 157 , 158 , 159 ]. However, the use of spheroids of different size can characterize the behavior of NK cells when challenged with tumors showing different mass density, or inner hypoxic areas [ 126 ].…”
Section: Tumor Cell Spheroids As a 3d Model To Study Tumor Cell Biology And Tumor-natural Killer Cross-talkmentioning
Several approaches have shown that the immune response against tumors strongly affects patients’ clinical outcome. Thus, the study of anti-tumor immunity is critical to understand and potentiate the mechanisms underlying the elimination of tumor cells. Natural killer (NK) cells are members of innate immunity and represent powerful anti-tumor effectors, able to eliminate tumor cells without a previous sensitization. Thus, the study of their involvement in anti-tumor responses is critical for clinical translation. This analysis has been performed in vitro, co-incubating NK with tumor cells and quantifying the cytotoxic activity of NK cells. In vivo confirmation has been applied to overcome the limits of in vitro testing, however, the innate immunity of mice and humans is different, leading to discrepancies. Different activating receptors on NK cells and counter-ligands on tumor cells are involved in the antitumor response, and innate immunity is strictly dependent on the specific microenvironment where it takes place. Thus, three-dimensional (3D) culture systems, where NK and tumor cells can interact in a tissue-like architecture, have been created. For example, tumor cell spheroids and primary organoids derived from several tumor types, have been used so far to analyze innate immune response, replacing animal models. Herein, we briefly introduce NK cells and analyze and discuss in detail the properties of 3D tumor culture systems and their use for the study of tumor cell interactions with NK cells.
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