In 3D tissues, the O2 concentration is not uniformly distributed but rather a gradient that depends on the distance from O2-carrying blood vessels. Thus, any rapid changes in O2 tension lead to steep gradients ranging from low to moderate O2 tension. Variations in O2 tension control signaling cascades that lead to metabolic and phenotypic changes. While the regulatory mechanisms are well studied, current understanding and the link to the tangible range of O2 tensions and gradients is limited.
We established novel O2-controlling hydrogel materials to serve as a 3D hypoxic microenvironment. Using mathematical modeling, we show that O2 levels and gradients within the hydrogels can be accurately controlled and precisely predicted. We demonstrated the regulatory mechanism underlying hypoxic vascular network formation and angiogenesis. We showed that hypoxia, through HIF 1 activation of metalloproteinase (MT1-MMP), enables matrix degradation, leading to vascular morphogenesis (1). Using this hydrogel system, we further found that cancer cells migrate towards higher O2 tension, demonstrating, for the first time, the physico-tactic properties of O2 (2,3). In recent works, we identified the mechanism undelaying hypoxic cluster-based vasculogenesis. We found that a rapid drop in O2 leads to reactive oxygen species production that up-regulates proteases and eventual endothelial cluster formation. Subsequently, endothelial sprouting into a stiffer, intact matrix leads to vascular network formation (4,5).
To our knowledge, no other biomaterial is capable of controlling or manipulating O2 in such a highly precise manner. This enables us to advance our understanding of how O2 tension gradients regulate developmental, regenerative, and tumorigenesis processes.
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- Lewis D, et al. Intratumoral oxygen gradients mediate sarcoma cell invasion. Proc Natl Acad Sci U S A. 2016; 113:9292-9297.
- Lewis DM*, Blatchley M*, Park KM, Gerecht S. O2-controllable hydrogels to study cellular responses to 3D hypoxic gradients. Nat Protoc. 2017; 12:1620-1638
- Blatchley MB, et al. Hypoxia and matrix viscoelasticity sequentially regulate endothelial progenitor cluster-based vasculogenesis. Sci Adv. 2019; 5:eaau7518.
- Blatchley MR, Hall F, Ntekoumes D, Cho H, Kailash V, Vazquez-Duhalt R, Gerecht S. Discretizing 3D Oxygen Gradients to Modulate and Investigate Cellular Processes. Adv Sci. 2021; e2100190.