# Human umbilical cord mesenchymal stem cell delivery of mitochondria to melanocytes enhances skin repigmentation efficacy in autologous epidermal cell suspension transplantation through the TNFAIP2-TNT system

## TL;DR

Adding stem cells to skin cell transplants improves repigmentation in mice by delivering mitochondria to pigment cells via a new pathway.

## Contribution

A novel TNFAIP2-TNT system is identified for mitochondrial delivery from stem cells to melanocytes, enhancing repigmentation.

## Key findings

- hUCMSCs enhance melanocyte proliferation, migration, and melanin synthesis in co-cultures and transplants.
- In vivo experiments show improved skin repigmentation in mice with hUCMSC co-transplantation.
- The TNFAIP2-TNT system mediates mitochondrial transfer to melanocytes, improving their function.

## Abstract

Autologous epidermal cell suspension (AECS) transplantation is essential for treating large-area depigmenting diseases and some chronic wounds that are refractory to conservative therapy. However, this technique encounters challenges, including limited repigmentation efficacy and high costs, which have hindered its clinical adoption. To enhance the repigmentation efficacy of AECS, our research explored the optimal conditions for preparing suspensions of epidermal cells (ECs). Next, we investigated the functions of melanocytes (MCs) and repigmentation efficacy through co-culturing and co-transplantation of human umbilical cord mesenchymal stem cells (hUCMSCs) with AECS. The addition of hUCMSCs to this system enhanced the proliferation, migration, and melanin synthesis capabilities of the ECs. These findings were validated in vivo, with the hUCMSCs co-transplantation group demonstrating superior skin repigmentation efficacy in mice. Then gene interference, overexpression, and transcriptome analyses were conducted to elucidate the mechanisms underlying the Tumor Necrosis Factor Alpha-Induced Protein 2 (TNFAIP2)-Tunneling Nanotubes (TNTs) system in mediating melanin synthesis. Our findings outline a novel pathway through which hUCMSCs, via the TNFAIP2-TNT system, mediate the delivery of mitochondria to melanocytes, enhancing the function of MCs. This presents new avenues for improving the repigmentation efficacy of AECS transplantation.