To help people suffering from a wide array of injuries and degenerative diseases, scientists and bioengineers have long dreamed of creating new joints and organs using human stem cells. A major hurdle on the path to achieving this dream has been finding ways to steer stem cells into differentiating into all of the various types of cells needed to build these replacement parts in a fast, efficient manner.
Now, an NIH-funded team of researchers has reported important progress on this front. The researchers have identified for the first time the precise biochemical signals needed to spur human embryonic stem cells to produce 12 key types of cells, and to do so rapidly. With these biochemical “recipes” in hand, researchers say they should be able to generate pure populations of replacement cells in a matter of days, rather than the weeks or even months it currently takes. In fact, they have already demonstrated that their high-efficiency approach can be used to produce potentially therapeutic amounts of human bone, cartilage, and heart tissue within a very short time frame.
The study, reported in the journal Cell, was led by students Kyle Loh and Angela Chen and senior authors Irving Weissman of Stanford University, Palo Alto, CA and Lay Teng Ang of the Genome Institute of Singapore. They were interested specifically in how embryonic stem cells commit to making cell types derived from the mesoderm, one of the initial embryonic germ layers. These include cell types found in skin, certain bones and muscles, connective tissues, and blood vessels.
Aided by science’s increased understanding of developmental biology and recent advances in sequencing RNA within individual cells, the team profiled the gene activity within individual embryonic stem cells in culture. This allowed them to look for any telltale changes in gene expression as undifferentiated stem cells commit to a cell lineage. From their analyses, they were able to compile the different sets of instructions to prompt these embryonic stem cells to make a total of 12 cell types, including heart, muscle, and bone .
The biochemical recipes were surprisingly straightforward, consisting of only a half dozen or so major biochemical ingredients in all. As has been demonstrated already in some model organisms, it’s the timing and correct sequence of those ingredients that is key.
By defining the right biochemical signal needed at the right time, the researchers found they could move the differentiation process along at a rapid pace, generating all of those dozen cell types in lab dishes in just 5 to 9 days. The researchers also defined a set of cell-surface markers that, like identification tags, enables them to recognize each cell type and track it.
The researchers then took the critical next step of confirming that the identified cells can indeed form functional replacement tissue. The researchers injected human bone cell progenitors under the skin of mice. Those cells went on to produce mineralized structures containing both bone and cartilage.
In another experiment, the researchers implanted human heart tissue into immunodeficient mice. Those human heart fragments continued beating in the animals for months. When the researchers subsequently transplanted stem cell-derived heart muscle cells into the animals, those cells established themselves in the implanted human heart tissue and remained there for a period of several weeks. The findings suggest that their approach to stem cell differentiation can rapidly produce cells that might one day be used to restore damaged heart tissue after a heart attack.
The paper has also provided some fundamental insights into human development in health and disease. For instance, the researchers used their gene expression data to identify cells that appear to be important for the development of congenital forms of scoliosis, a condition characterized by abnormal spinal curvature.
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.
 Mapping the pairwise choices leading from pluripotency to human bone, heart, and other cell types. Loh KM, Chen A, Koh PW, Deng TZ, Sinha R, Tsai JM, Barkal AA, Shen KY, Jain R, Morganti RM, Shyh-Chang N, Fernhoff NB, George BM, Wernig G, Salomon RE, Chen Z, Vogel H, Epstein JA, Kundaje A, Talbot WS, Beachy PA, Ang LT, Weissman IL. Cell. 2016 Jul 14;166(2):451-467.
Stem Cell Information (NIH)
Institute for Stem Cell Biology and Regenerative Medicine (Stanford University, Palo Alto, CA)
NIH Support: National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences; National Institute of Neurological Disorders and Stroke