Senescent fibroblasts, not neurons, triggered post-chemotherapy neuropathy in animal experiments

In mouse experiments, skin fibroblasts triggered post-chemotherapy neuropathy

On 5 August, bioRxiv published a preprint, a version of a scientific paper that has not yet undergone peer review. The authors investigated how paclitaxel and cisplatin cause peripheral neuropathy in mice, a form of nerve damage that alters sensation. In skin biopsies from six patients with this neuropathy, they also found more fibroblasts showing signs of senescence than in three matched control participants.

In these models, nerve endings in the skin degenerated. When an axon, the long projection of a neuron, is damaged, the enzyme SARM1 consumes NAD+, a molecule involved in cellular energy supply, and initiates axon degeneration. The authors investigated which process activates SARM1 after chemotherapy.

After paclitaxel treatment, signs of senescence appeared in the skin of the mice's paws. In this state, cells stop dividing and change the set of signals they release. Single-cell RNA analysis linked these signs to dermal fibroblasts, connective tissue cells located near nerve endings. The researchers first genetically eliminated all cells with these signs and then eliminated only fibroblasts with these signs. In both experiments, the mice retained their nerve endings and normal sensitivity to touch.

In mice without SARM1, senescent fibroblasts still appeared after chemotherapy, while innervation and sensitivity remained intact. Based on this sequence, the authors placed the changes in fibroblasts upstream of SARM1 in the causal chain.

The authors then examined how these cells transmit the harmful signal. MK2 is a signaling pathway protein that the authors linked to SASP, the set of molecules released by senescent cells. When the researchers disabled MK2 throughout the body or only in fibroblasts, cells showing signs of senescence remained, while axons and sensitivity were preserved. When symptoms had already developed in the mice, eliminating senescent cells, administering a combination of dasatinib and quercetin, or inhibiting MK2 restored innervation and sensitivity. The authors place MK2-dependent fibroblast signaling upstream of SARM1 and the degeneration of nerve endings.