Tissue Healing Mechanisms

Partial Reprogramming

Partial reprogramming is a form of epigenetic reprogramming that assists in tissue healing. It temporarily induces a pluripotent state in cells, aiding lifespan extension and tissue regeneration.

Partial reprogramming achieved by the transient expression of the transcription factors (TFs) Oct4, Sox2, Klf4 and C-Myc (abbreviated OSKM) can erase aging and damage features in cells, leading to increased healthspan, lifespan and tissue regeneration. Recent reports suggest that the mechanisms of partial reprogramming may share some similarities with natural dedifferentiation and regeneration. Both processes appear to involve the transient repression of somatic identity through the sequestration of somatic identity TFs to noncanonical sites, which are opened by the high expression of pioneer TFs, leading to transient dedifferentiation into a fetal-like state.

Sahu et al. (2024) demonstrated that targeted partial reprogramming with Oct4, Sox2, and Klf4 (OSK) delivered via adeno-associated virus (AAV) to Cdkn2a-positive cells can rejuvenate senescent cells while maintaining cellular identity. This approach has shown promising results in both progeroid and naturally aged mouse models, leading to improved lifespan, reduced inflammation, restored tissue integrity, and enhanced wound healing.

Aryl Hydrocarbon Receptor

The Aryl Hydrocarbon Receptor (AHR) is a receptor protein found inside cells that plays a critical role in the immune response and tissue healing. It also has a critical role in immune response and interaction with external factors, which holds promise for novel disease treatments.

Insufficient AHR activation can result in an immune system imbalance, leading to diseases. Restoring AHR activity has shown promise in aiding wound healing and treating autoimmune diseases.

In lupus, for example, insufficient activation of AHR results in too many disease-promoting immune cells, called the T peripheral helper cells, that promote the production of disease-causing autoantibodies. To show this discovery can be leveraged for treatments, the investigators returned the aryl hydrocarbon receptor-activating molecules to blood samples from lupus patients. This seemed to reprogram these lupus-causing cells into a cell called a Th22 cell that may promote wound healing from the damage caused by this autoimmune disease.