# Mfsd2a is important for maintaining epidermal homeostasis

## TL;DR

This study shows that Mfsd2a helps skin cells take up a type of phospholipid, which is important for maintaining healthy skin and preventing conditions like eczema.

## Contribution

The study identifies Mfsd2a as a key transporter for lysophosphatidylcholines in epidermal keratinocytes, linking it to epidermal homeostasis.

## Key findings

- Mfsd2a deficiency in mice leads to dermatitis and impaired epidermal desquamation.
- Mfsd2a is crucial for keratinocyte uptake of plasma-derived lysophosphatidylcholines.
- LPCs promote keratinocyte differentiation in a Mfsd2a-dependent manner in human cells.

## Abstract

Disruption of the epidermal skin barrier is a common clinical feature for prevalent diseases such as atopic dermatitis and psoriasis. Epidermal function is reliant on dietary linoleic acid and has a high demand for phospholipids, but whether epidermal keratinocytes take up plasma-derived phospholipid such as the abundant plasma lysophosphatidylcholines (LPC) is not known. This study utilized mouse models of epidermal Mfsd2a deficiency, histological and gene expression analysis, untargeted lipidomics, and human keratinocyte cultures, demonstrating that the epidermal keratinocytes acquire plasma-derived LPC via Mfsd2a mediated transport; and this pathway is important for maintaining a normal phospholipidome and proper epidermal differentiation. The findings in this study raise the possibility that LPCs might have therapeutic benefit for epidermal health.

The skin epidermis is a multilayered lipid rich organ completely reliant on exogenous delivery and uptake of the essential fatty linoleate for the synthesis of acylceramides required for barrier function. Disruption of the epidermal skin barrier is a common clinical feature for prevalent diseases such as atopic dermatitis and psoriasis. The granulosum layer of the epidermis contains specialized secretory keratinocytes that synthesize and secrete lamellar bodies (LB), making it likely that this epidermal layer has a high demand for phosphatidylcholine. While the pathway for acylceramide biosynthesis and roles in barrier formation has been largely elucidated, the mechanisms by which keratinocytes acquire phospholipid for the demands of lipid barrier maintenance and repair are not entirely understood. Here, we demonstrate that Mfsd2a, a lysophosphatidylcholine (LPC) transporter, is predominantly expressed in keratinocytes and mediates the uptake of a plasma-derived LPC fluorescent probe. Epidermal-specific deficiency of Mfsd2a in mice resulted in dermatitis and defective desquamation of the epidermis, and inducible deletion of Mfsd2a in primary mouse keratinocytes in vitro prevented their epidermal stratification. Untargeted lipidomic analysis indicated that Mfsd2a deficiency resulted in a significantly altered phospholipidome, with specific reductions in linoleic acid in phosphatidylcholine and triglycerides in the epidermis. Functional studies using primary human keratinocytes demonstrated that LPC-oleate and LPC-linoleate promoted keratinocyte differentiation in a Mfsd2a-dependent manner. Our findings identify a pathway by which keratinocytes acquire plasma-derived LPC via Mfsd2a transport for the maintenance of normal keratinocyte phosphatidylcholine pools and for optimal keratinocyte differentiation.