Nature Biotechnology: hPSCs can be restored to a state that supports reproducible differentiation

Chemical treatment restored the ability of some stem cells to generate brain, kidney, and intestinal models

In a paper published on 7 August in Nature Biotechnology, researchers explained why human pluripotent stem cells produce different tissues under identical conditions. In some cell lines, chemical restoration of chromatin reinstated this capacity in three-dimensional tissue models.

Human pluripotent stem cells can give rise to almost any tissue. In the laboratory, researchers direct them along a chosen developmental path. For example, they can grow a brain organoid, which is a three-dimensional cellular model of developing neural tissue.

Identical conditions can sometimes produce different results. Two cell lines may grow in the same medium and receive the same signals, yet one forms a recognizable brain model while the other consists mainly of cells following a different developmental program. In the paper published on 7 August, the authors linked this variability to a memory of an early stage of embryonic development.

The epiblast is a layer of cells in the early embryo that later gives rise to the tissues of the body. In cell lines that formed brain organoids poorly, some developmental genes had already been activated in a pattern resembling the posterior epiblast. Other developmental genes had lost their bivalent chromatin marks, a combination of two chemical modifications on the DNA packaging. A gene with these marks remains silent but retains the capacity to become active when it receives the appropriate signal.

The authors exposed the cells to a sequence of media containing small chemical compounds and called the procedure chemical chromatin restoration, CHR. After treatment, the chromatin patterns and gene activity of previously problematic cell lines became more similar to those of lines that differentiated efficiently into the intended tissues. The treated cells then formed brain organoids and, under other conditions, kidney and intestinal models. The authors therefore tested the result across three distinct paths of cell development.

Madeline Lancaster is among the authors of the paper. In 2013, she was the first author of a study that used human pluripotent cells to create three-dimensional models of brain development and microcephaly. The new paper adds another control step to this type of model: assessing the state of the starting cell line before directing the cells toward the intended tissue.

The state of the starting cell line can be assessed before an organoid is grown. Researchers can determine whether developmental genes remain ready to respond to the appropriate signal and, in some lines, restore that readiness through chemical preparation.