Theranostics 2019; 9(18):5200-5213. doi:10.7150/thno.31526

Research Paper

Spontaneous evolution of human skin fibroblasts into wound-healing keratinocyte-like cells

Fang Zhang1,2*, Dandan Zhang3*, Kai Cheng1,3*, Zaixin Zhou1*, Shupeng Liu1,3, Liang Chen1, Yijun Hu1,3, Chuanbin Mao4✉, Shanrong Liu1✉

1. Department of Laboratory and Diagnosis, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
2. No. 73901 troops, Shanghai 200439, China.
3. Clinical Research Center, Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
4. Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, Institute for Biomedical Engineering, Science and Technology, University of Oklahoma, 101 Stephenson Parkway, Norman, Oklahoma 73019-5300, USA.
* These authors contributed equally to this work.

Abstract

Producing keratinocyte cells (KCs) in large scale is difficult due to their slow proliferation, disabling their use as seed cells for skin regeneration and wound healing. Cell reprogramming is a promising inducer-based approach to KC production but only reaches very low cellular conversion. Here we reported a unique cellular conversion phenomenon, where human skin fibroblasts (FBs) were spontaneously converted into keratinocyte-like cells (KLCs) over the time without using any inducers.

Methods: FBs were routinely cultured for more than 120 days in regular culture medium. Characteristics of KLCs were checked at the molecular and cellular level. Then the functionality and safety of the KLCs were verified by wound healing and tumorigenicity assay, respectively. To identify the mechanism of the cell conversion phenomenon, high-throughput RNA sequencing was also performed.

Results: The global conversion started on day 90 and reached 90% on day 110. The KLCs were as functional and effective as KCs in wound healing without causing oncogenicity. The conversion was regulated via a PI3K-AKT signaling pathway mediated by a long non-coding RNA, LINC00672. Modulating the pathway could shorten the conversion time to 14 days.

Conclusion: The discovered FBs-KLCs conversion in the study might open a new avenue to the scalable production of cell sources needed for regenerating skins and healing large-area wounds.

Keywords: cellular conversion, time-dependent, fibroblasts, keratinocyte-like cells, wound healing

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How to cite this article:
Zhang F, Zhang D, Cheng K, Zhou Z, Liu S, Chen L, Hu Y, Mao C, Liu S. Spontaneous evolution of human skin fibroblasts into wound-healing keratinocyte-like cells. Theranostics 2019; 9(18):5200-5213. doi:10.7150/thno.31526. Available from http://www.thno.org/v09p5200.htm