Redox regulation in regenerative medicine and tissue engineering: The paradox of oxygen

Abstract

One of the biggest challenges in tissue engineering and regenerative medicine is to incorporate a functioning vasculature to overcome the consequences of a lack of oxygen and nutrients in the tissue construct. Otherwise, decreased oxygen tension leads to incomplete metabolism and the formation of the so-called reactive oxygen species (ROS). Cells have many endogenous antioxidant systems to ensure a balance between ROS and antioxidants, but if this balance is disrupted by factors such as high levels of ROS due to long-term hypoxia, there will be tissue damage and dysfunction. Current attempts to solve the oxygen problem in the field rarely take into account the importance of the redox balance and are instead centred on releasing or generating oxygen. The first problem with this approach is that although oxygen is necessary for life, it is paradoxically also a highly toxic molecule. Furthermore, although some oxygen-generating biomaterials produce oxygen, they also generate hydrogen peroxide, a ROS, as an intermediate product. In this review, we discuss why it would be a superior strategy to supplement oxygen delivery with molecules to safeguard the important redox balance. Redox sensor proteins that can stimulate the anaerobic metabolism, angiogenesis, and enhancement of endogenous antioxidant systems are discussed as promising targets. We propose that redox regulating biomaterials have the potential to tackle some of the challenges related to angiogenesis and that the knowledge in this review will help scientists in tissue engineering and regenerative medicine realize this aim.

Keywords: HIF; Nrf2; bone; heart; oxygen; pancreas; redox; redox regulating biomaterials.

Figure 1

(a) Alpha and beta cells are organized in the highly vascularized islets of Langerhans in a healthy human pancreas, and their functions include maintaining balanced glucose levels. Alpha cells release glucagon in response to low blood glucose levels, ensuring sufficient energy supply in periods of starvation, whereas insulin is released by the beta cells directly after a meal, inducing storage of excess glucose. (b) In type 1 diabetes, the immune system attacks the beta cells, (c) and one option for a cure is a bioengineered pancreas of encapsulated islets of Langerhans that can be implanted at different sites (e.g., liver, peritoneum, or subcutaneous). However, because of reduced angiogenesis and subsequent low oxygen and nutrients levels, the transplanted cells may not function properly

Figure 2

(a) In physiological conditions, cells have a tightly regulated and highly dynamic redox balance to maintain an equilibrium between oxidants and antioxidants. The cell is continuously exposed to different endogenous and exogenous oxidant and antioxidant challenges, but with endogenous oxidant generators and modulation of endogenous antioxidant systems, the cell is capable of maintaining the balance. (b) When the cell is exposed to more oxidants than the endogenous antioxidant systems can handle, this can disrupt the balance and induce a phenomenon called oxidative stress. This can happen, for example, when cells are exposed to an excess of oxygen, called hyperoxia. Hyperoxia dramatically increases the rate of aerobic metabolism, resulting in the generation of reactive oxygen species (ROS) due to incomplete metabolism, which in turn disrupts the redox balance and results in damage to cellular macromolecules, including DNA, lipids, and proteins. (c) The redox balance can be restored by targeting endogenous modulators of the endogenous antioxidant systems. For example, enhancement of the transcription factor Nrf2 increases (basal) levels of endogenous antioxidant systems (Sthijns et al., 2017), whereas increasing the transcription factor hypoxia inducible factor (HIF) induces anaerobic metabolism, stimulates angiogenesis, and increases glutaminase‐mediated glutathione synthesis, thereby enhancing endogenous antioxidant systems (Stegen, van Gastel, et al., 2016; Thirlwell, Schulz, Dibra, & Beck, 2011)

Figure 3

(a) A superior strategy for redox modulation could be to design a biomaterial that releases a drug in presence of excess reactive oxygen species (ROS) or oxidative stress. (b) The molecular targets are the redox sensor transcription factors Nrf2 and hypoxia inducible factor (HIF). By modulating Nrf2, the regulation of endogenous antioxidant systems (Sthijns et al., 2017) is induced, resulting in restoration of the redox balance. HIF activation increases anaerobic metabolism, stimulates angiogenesis, and increases glutaminase‐mediated glutathione synthesis, thereby enhancing endogenous antioxidant systems to recover the redox balance (Stegen, van Gastel, et al., 2016; Thirlwell et al., 2011). (c) Introducing Nrf2 and HIF enhancers in a biomaterial for pancreatic islets could prevent damage from oxidative stress, induce alternative metabolic pathways to ensure a sufficient energy supply, and enhance angiogenesis