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MXD4/MAD4 : a target of interest for ex vivo stem cell preservation

The clinical efficacy of bioengineered skin grafts is directly tied to the amount of functional stem cells they contain. In a study published in the Journal of Investigative Dermatology, researchers from LGRK (iRCM) identified the transcription factor MXD4/MAD4 as an element of the pathway regulating the stemness of keratinocyte precursors and their skin regeneration capacities. The factor thus represents a novel molecular target for optimizing the preservation of skin stem cells during ex vivo expansion, upstream of three-dimensional cutaneous reconstruction.

Published on 3 February 2023

The field of human skin substitute bioengineering is empowering great strides in regenerative medicine with such advances as permanent grafts for burn victims and biological dressings for the treatment of chronic ulcers. A major challenge in that field is reconstituting the skin's outermost epidermal layer, which provides the vital barrier function for the organism. The epidermis is a constantly renewing epithelial tissue composed mostly of keratinocytes. Its long-term integrity depends on specific stem cells residing within it, called, fittingly, epidermal or keratinocyte stem cells (KSTs).

Thus, the preservation of KSTs during the fabrication of bioengineered skin grafts is critical for the clinical function of these latter. Preserving KSTs is particularly vital during the ex vivo cellular expansion phase, which precedes the three-dimensional cutaneous reconstruction phase. Thus, a fine understanding of the molecular networks involved in controlling the biological properties and functions of KSTs is a key goal in the field of skin tissue therapies.

To help attain that goal, researchers from the Genomics and Radiobiology of Keratinopoiesis Laboratory (LGRK/iRCM) turned their attention to a transcription factor called MXD4/MAD4. In their work carried out in partnership with the Percy Army Hospital's blood transfusion center and published in the Journal of Investigative Dermatology, the team positioned this factor as a novel element playing a key role in the regulation of the stem-cell status, or "stemness" of human KSTs.

Using interfering RNA to modulate the factor (repressing the expression of the gene MXD4 coding for the protein MAD4), the team obtained mitotic activity in the KSTs with maintenance of their functionality: long-term proliferation capacities, clonogenicity and aptitudes for forming a correctly differentiated three-dimensional epithelial sheet.

Furthermore, they reported the conservation of the molecular signatures characteristic of stem cells capable of regenerating the epidermis (i.e. "holoclone" cells).

Thus, the MXD4/MAD4 transcription factor appears to be a pertinent molecular target for the development of tools to increase the optimization and reliability of the ex vivo expansion of functional skin stem cells in the setting of skin graft bioengineering for cutaneous repair.

Contact researcher CEA : Nicolas Fortunel

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