Chronic degenerative failure of salivary glands can be reversed through restoring mitochondrial function.

There are no therapies for reversing chronic organ degeneration. Non-healing degenerative wounds are thought to be irreparable, in part, by the inability of the tissue to respond to reparative stimuli. As such, treatments are typically aimed at slowing tissue degeneration or replacing cells through transplantation. Building on our previous studies showing acutely injured salivary glands, and specifically secretory acini, can be regenerated, we reveal that non-healing, degenerating murine salivary glands remain responsive to a neuromimetic (muscarinic) agonist with treatment resulting in the restoration of tissue. Not only is degenerated tissue structure and function returned to a homeostatic-like state, but this outcome is also sustained months after treatment termination. Furthermore, despite an eventual reduction in saliva secretion, the gland responds to a second round of treatment, fully regaining secretory function that resembles uninjured controls. Our findings suggest this rescue is due to a reversal of an aberrant de-differentiated acinar cell state and mitochondrial dysfunction through a muscarinic-calcium signaling pathway. Thus, these data challenge the concept that organ degeneration is irreversible and provides a readily testable therapeutic strategy for epithelial organ restoration that may significantly benefit a diversity of chronic disease conditions.