Impelling force and current challenges by chemicals in somatic cell reprogramming and expansion beyond hepatocytes

Abstract

In the field of regenerative medicine, generating numerous transplantable functional cells in the laboratory setting on a large scale is a major challenge. However, the in vitro maintenance and expansion of terminally differentiated cells are challenging because of the lack of specific environmental and intercellular signal stimulations, markedly hindering their therapeutic application. Remarkably, the generation of stem/progenitor cells or functional cells with effective proliferative potential is markedly in demand for disease modeling, cell-based transplantation, and drug discovery. Despite the potent genetic manipulation of transcription factors, integration-free chemically defined approaches for the conversion of somatic cell fate have garnered considerable attention in recent years. This review aims to summarize the progress thus far and discuss the advantages, limitations, and challenges of the impact of full chemicals on the stepwise reprogramming of pluripotency, direct lineage conversion, and direct lineage expansion on somatic cells. Owing to the current chemical-mediated induction, reprogrammed pluripotent stem cells with reproducibility difficulties, and direct lineage converted cells with marked functional deficiency, it is imperative to generate the desired cell types directly by chemically inducing their potent proliferation ability through a lineage-committed progenitor state, while upholding the maturation and engraftment capacity posttransplantation in vivo. Together with the comprehensive understanding of the mechanism of chemical drives, as well as the elucidation of specificity and commonalities, the precise manipulation of the expansion for diverse functional cell types could broaden the available cell sources and enhance the cellular function for clinical application in future.

Keywords: Chemical induction; Pluripotent reprogramming; Direct lineage conversion; Direct lineage expansion; Hepatocyte expansion; Cell fate specificity; Transcriptional memory; In vivo induction

Core tip: Chemical-mediated reprogramming is a promising strategy for generating desired cells. However, chemical-mediated pluripotent reprogramming has reproducibility difficulties, and direct lineage conversion shows significant deficiency in cell function maturation. On the other hand, direct lineage expansion from target cells not only bypasses pluripotency-related tumorigenesis but also has superior posttransplantation advantages in engraftment and functional maturation. Recent achievements in chemical expansion of human hepatocytes may help solve the cell source limitation in liver disease treatment.