Imagine coaxing immature bone cells into maturity to heal fractures or using heart muscle cells to mend damage after a heart attack. This isn’t the topic of some futuristic medical drama. Starter instructions to execute this regenerative transformation were published earlier this summer in a multi-institution study, including scientists who study cardiology at the Perelman School of Medicine. They described a road map in the journal Cell outlining how to cajole human embryonic stem cells (which have the potential to become hundreds of different cell types) into immature bone, heart, and muscle cells, among 12 cell types studied in total.
A Stanford Medicine group led by Irving Weismann, MD, head of the Institute for Stem Cell Biology there, hastened this transformative process from weeks to days. Turning human stem cells, which innately can become many different mature cell types, into specifically desired categories of cells -- in a matter of days – and that can safely be used in patients is a paramount goal of regenerative medicine. The study’s emphasis was on achieving a short timeframe and uniform populations of a desired cell type.
However, getting to this goal takes patience and the contributions of legions, including the labs of
Rajan Jain, MD, an assistant professor of Medicine, and
Jon Epstein, MD, executive vice dean and chief scientific officer for Penn Medicine. The team, using human embryonic stem cells, ascertained through a series of intricate experiments that the cells advance through many two-way “choices,” to eventually become a mature heart, nerve, or bone cell, for example. This
whiteboard video from Cell Press explains in a quick four minutes how the team pushed stem cells to take one path or another at various forks in the developmental road. They also confirmed that they made pure populations of each cell type using single cell RNA sequencing. (Before this study, researchers could only produce a mixed bag of cells, which most of the time were not all the same type.)
But the team needed to prove that the essentially pure human cell populations could indeed generate the desired cell types and be functional. Jain addressed this in the HopX mouse model he developed with Epstein. With this model, researchers can indelibly mark all HopX-positive cells in a mouse and identify all derived cell populations going forward. Previous studies from the Epstein laboratory have implicated HopX in regulating gene expression.
In 2015, Jain and Epstein thought that the protein HopX would label a multi-potent progenitor cell, but they were surprised to learn that it was marking only the cells that were going on to make heart muscle. They described this in a cover article of Science.
Previously, they had learned that HopX is expressed in multiple adult stem cells, including those of the intestine, hair follicle, and brain. The Penn and Stanford groups collaborated to show that HopX marks bone progenitors, which gave rise to bone and cartilage cells in mouse and human models. This validated the function and capabilities of the group’s cells.
Collectively, the team’s roadmap shows how to steer one type of human embryo cell population down a series of choices to make specific types of cells. “This furthers our ability to one day produce transplantable human progenitor cells for patients,” Jain said.
With an appropriate bibliometaphor, the NIH Director’s Blog, concluded that, “these findings potentially mark an important step forward for regenerative medicine. With about 200 cell types in the human body, there is still a ways to go before our instruction book for cell differentiation is complete. But it’s great to see these new recipes, and we look forward to the publication of many more chapters.”
For next steps, Jain has continued his collaboration with the Weissman group to plot points on the branching tree of human development by mapping the epigenetic molecules that instruct cell fate. “This exciting collaboration will undoubtedly shed light on how cells make these ‘two-way’ decisions and refine our ability to make cell types of interest at will,” Jain said.
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