Hypoxic signaling during tissue repair and regenerative medicine

Abstract

In patients with chronic wounds, autologous tissue repair is often not sufficient to heal the wound. These patients might benefit from regenerative medicine or the implantation of a tissue-engineered scaffold. Both wound healing and tissue engineering is dependent on the formation of a microvascular network. This process is highly regulated by hypoxia and the transcription factors hypoxia-inducible factors-1α (HIF-1α) and -2α (HIF-2α). Even though much is known about the function of HIF-1α in wound healing, knowledge about the function of HIF-2α in wound healing is lacking. This review focuses on the function of HIF-1α and HIF-2α in microvascular network formation, wound healing, and therapy strategies.

Figure 1

A schematic overview of the phases of wound healing over time. After the initial hemostasis phase, neutrophils and macrophages dominate the inflammation phase, whereas fibroblasts and endothelial cells are predominant during the proliferation phase. During the remodeling phase, fibroblasts and endothelial cells undergo apoptosis or exit the wound. Finally, the granulation tissue and vascular network remodel and mature, which can last for years. The dotted blue line indicates the time course of oxygen availability.

Figure 2

A schematic representation of the domain structures of the HIFs. The figure shows the structural motifs basic-Helix-Loop-Helix (bHLH, in blue), PER/ARNT/SIM (PAS, in yellow), the oxygen-dependent degradation domain (ODDD, in green and also spanning the N-TAD region), the N-terminal and C-terminal transactivation domains (N-TAD and C-TAD, in pink), and the leucine zipper (LZIP, in white). The positions of the prolines hydroxylated by PHDs (prolyl-hydroxylase domain containing enzymes) are indicated by P and the asparagines hydroxylated by FIH (factor inhibiting HIF) are indicated by N. Adapted from [47].

Figure 3

A schematic representation of the oxygen-dependent regulation of HIF-α. During normoxia, HIF-α is hydroxylated by prolyl hydroxylase domain proteins (PHDs) on proline residues. These proline residues are recognized by the protein Von Hippel Lindau (pVHL), which results in proteasomal degradation. Upon hypoxia, HIF-α is not hydroxylated and subsequently translocated to the nucleus. In the nucleus, HIF-α heterodimerizes with HIF-β; this allows the co-factors p300 and Creb-binding protein (CBP) to bind to the heterodimer. The complex binds to the hypoxia-responsive elements (HRE) and thereby induces gene expression. Adapted from [60].