Abstract
Human adipose-derived stem cells (hADSCs) spheroids have displayed remarkable potential for treating ischemic injury. However, low nutrient (i.e., glucose and oxygen) availability in ischemic environments results in limited tissue viability posttransplantation. To develop a mechanistic understanding of nutrient levels on spheroid survival, we used an in vitro culture system to investigate the effects of varying glucose and oxygen concentrations on the cellular viability of hADSC spheroids with varied radii (115–215 μm). Our data showed that low viability can be improved with higher levels of glucose, but not with enhanced availability of oxygen. To understand the experimental results, we established a computational model to simulate nutrient diffusion and metabolism in hADSC spheroids at different glucose and oxygen concentrations. By combining experimental data and modeling results, we established a strong linear correlation (R2 = 0.84) between spheroid glucose availability (i.e., spheroid volume with available glucose) and spheroid viability. In contrast, increasing oxygen availability had negligible impact on spheroid viability, suggesting a greater dependence on anaerobic glycolysis for adenosine triphosphate generation as opposed to oxidative phosphorylation. These data demonstrated the critical role of glucose in hADSC spheroid survival under ischemia. These results may impact future strategies for improving hADSC transplantation efficacy through codelivery of metabolic substrates.
Impact Statement
Human adipose-derived stem cells (hADSCs) spheroids have displayed remarkable potential for treating ischemic injury. However, low nutrient (i.e., glucose and oxygen) availability in ischemic environments results in limited tissue viability posttransplantation. To develop an understanding of the effects of nutrient availability on spheroid survival, we utilized both in vitro and computational models to examine the limiting factors in metabolic supply for avascular microtissues, revealing the critical role of glucose to improve hADSC spheroid survival in ischemic conditions. These results may impact future strategies for improving hADSC transplantation efficacy through codelivery of metabolic substrates.
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