Researchers at the Salk Institute report the discovery of a new type of pluripotent stem cell whose identity is tied to its location in a developing embryo. This contrasts with stem cells traditionally used in scientific study, which are characterized by their time-related stage of development.

In a paper (“An alternative pluripotent state confers interspecies chimaeric competency”) published in Nature, the scientists discuss using these new stem cells to develop the first reliable method for integrating human stem cells into nonviable mouse embryos in a laboratory dish in such a way that the human cells began to differentiate into early-stage tissues.

“The region-specific cells we found could provide tremendous advantages in the laboratory to study development, evolution and disease, and may offer avenues for generating novel therapies,” says Juan Carlos Izpisua Belmonte, Ph.D., senior author of the paper and holder of Salk's Roger Guillemin Chair.

The researchers dubbed this new class of cells “region-selective pluripotent stem cells,” or rsPSCs for short. The rsPSCs were easier to grow in the laboratory than conventional human pluripotent stem cells and offered advantages for large-scale production and gene editing.

To produce the cells, the Salk scientists developed a combination of chemical signals that directed human stem cells in a lab dish to become spatially oriented. They then inserted these human rsPSCs into specific regions of partially dissected mouse embryos and cultured them in a dish for 36 hours. Separately, they also inserted human stem cells cultured using conventional methods, so that they could compare existing techniques to their new technique.

“…by modulating culture parameters, a stem-cell type with unique spatial characteristics and distinct molecular and functional features, designated as region-selective pluripotent stem cells (rsPSCs), can be efficiently obtained from mouse embryos and primate pluripotent stem cells, including humans,” wrote the investigators.

While the human stem cells derived through conventional methods failed to integrate into the modified embryos, the human rsPSCs began to develop into early-stage tissues. The cells in this region of an early embryo undergo dynamic changes to give rise to all cells, tissues, and organs of the body. Indeed the human rsPSCs began the process of differentiating into the three major cell layers in early development (ectoderm, mesoderm, and endoderm). The Salk researchers stopped the cells from differentiating further, but each germ layer was theoretically capable of giving rise to specific tissues and organs.

The scientists said they performed extensive characterization of the new cells and found that rsPSCs showed distinct molecular and metabolic characteristics as well as novel epigenetic signatures.

“The region selective-state of these stem cells is entirely novel for laboratory-cultured stem cells and offers important insight into how human stem cells might be differentiated into derivatives that give rise to a wide range of tissues and organs,” says Jun Wu, Ph.D., a postdoctoral researcher in Izpisua Belmonte's lab and first author of the new paper. “Not only do we need to consider the timing, but also the spatial characteristics of the stem cells. Understanding both aspects of a stem cell's identity could be crucial to generate functional and mature cell types for regenerative medicine.”

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