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.

Human liver model systems in a dish

“…Of note is the method of direct reprogramming of fibroblasts into hepatocyte‐like cells that are functionally active (Du et al., 2014; Huang et al., 2014; Sekiya & Suzuki, 2011; Xie et al., 2019). This method holds another promise towards regenerative studies and has been reviewed elsewhere (Ge et al., 2019).…”

Hepatitis B virus infection modeling using multi-cellular organoids derived from human induced pluripotent stem cells

“…Using chemical induction, a limited expansion capability of human hepatocytes was successfully induced in 2D monolayer culture systems[ 67 , 68 ]. However, expansion in a 3D system is subjected to complicated factors, such as nutrient/gas exchange, contact inhibition, and complex cell-cell signaling.…”

Practical choice for robust and efficient differentiation of human pluripotent stem cells

“…Most 3D culture methods involve various intermediate stages requiring varying combinations of recombinant factors and small molecules[ 63 ], thus rendering the method cumbersome to repeat. Although TF-mediated methods improve the differentiation efficiency of hPSCs, numerous tools for TF transfection, including plasmids and viruses, have led to the integration of exogenetic genes[ 66 ] into the target cells, thus presenting a remote prospects for their clinical application[ 56 ]. In this situation, EB-based 3D culture systems allow for large-scale directional differentiation of hPSCs, and the co-culture method seems to constitute highly functional organoids in vitro to compensate for organ transplantation insufficiency.…”