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Researchers discover new type of stem cell.

A Mount Sinai-led research team has discovered a new kind of stem cell that can become either a liver cell or a cell that lines liver blood vessels. The existence of such a cell type contradicts current theory on how organs arise from cell layers in the embryo, and may hold clues to origins of, and future treatment for, liver cancer.  The opensource study is published in the journal Stem Cell Reports.

Thanks to stem cells, humans develop from a single cell into a complex being made up of more than 200 cell types. The original, single human stem cell, the fertilized embryo, has the potential to develop into every kind of human cell. Stem cells multiply (proliferate) and specialize (differentiate) until millions of functional cells result, including liver cells (hepatocytes), blood vessel cells (endothelial cells), muscle cells, bone cells, etc.

In the womb, the human embryo early on becomes three germ layers of stem cells, the endoderm, mesoderm and ectoderm. The long-held consensus was that the endoderm goes on to form the liver and other gut organs; the mesoderm the heart, muscles and blood cells; and the ectoderm the brain and skin. Researchers have sought to determine the germ layer that yields each organ because these origins hold clues to healthy function and disease mechanisms in adults.

The team found a stem cell that can become either a liver cell, which is thought to originate in the endoderm, or an endothelial cell that helps to from a blood vessel, which was thought to derive from the mesoderm.  The current results go against traditional germ layer theory, which holds that a stem cell can only go on to become cell types in line with the germ layer that stem cell came from. Endothelial cells may arise from both the endoderm and mesoderm.

Beyond the womb, many human organs contain pools of partially differentiated stem cells, which are ready to differentiate into specific replacement cells as needed. Among these are stem cells that know they are liver cells, but have enough stemness to become more than one cell type.

By advancing the understanding of stem cell processes in the liver, the study offers insights into mechanisms that drive liver cancer. The rapid growth seen in cells as the fetal liver develops is similar in some ways to the growth seen in tumors. Among the factors that make both possible is the building of blood vessels that supply nutrients and oxygen.

The research team’s newfound, liver-based stem cell type has the ability to become part of newly formed blood vessels. Thus, a detailed understanding of it may have a decisive impact on understanding liver cancer progression. If similar bi-potential progenitor cells are found in liver cancers, they may be ideal targets for drugs that eradicate not only their descendant liver cancer cells but also the formation of blood vessels that feed tumours.

The new study also has implications for the field of liver regeneration. Many labs seek to understand how the liver repairs itself when damaged, and many clinical trials to determine whether injecting healthy liver cells into damaged livers can repair them.

Within limits, mature liver cells divide and multiply to supply new cells that replace damaged ones. When the damage is too severe, however, evidence suggests that the organ calls on its stem cell pool, with stem cells multiplying to provide additional replacement cells.  The researchers theorize that their new stem cell type has a role here as well, and further studies are underway to test its therapeutic potential. Using standard tools of molecular biology, the team garnered evidence that the newly discovered stem cell type is present in both human and mouse livers as a fetus develops, and that these cells have a regenerative effect when transplanted into damaged mouse livers.

Source:  The Mount Sinai School of Medicine

 

FOXA2+ Cell Contribution to Fetal Liver ECs in Two Foxa2 Lineage-Tracing Mouse Models.  (A–C) IF of fetal liver sections from E12.5 YFPpos embryos of Foxa2-iCre;YFP mice (×200). White arrows indicate the YFP+CD31+ ECs, and yellow arrowheads indicate the YFP-CD31+ hematopoietic cells.  (D) Flow analyses from four E13.5 YFPpos fetal livers and one E13.5 YFPneg fetal liver of Foxa2-iCre;YFP mice. Numbers indicate the mean ± SD of the percentage of cell populations in each gate for four YFPpos embryos.  (E) FOXA2 and YFP IF on E8.5 embryo section of Foxa2-CreTAM;YFP mice. Large image shows the tiling of a whole E8.5 embryo. The small image is a close-up of the foregut endoderm (×100).  (F) IF of YFP and KDR at E8.5 of Foxa2-CreTAM;YFP mice (×200). White arrows indicate rare YFP+KDR+ cells.  (G–I) IF for YFP and CD31 of E12.5 fetal liver sections from Foxa2-CreTAM;YFP mice (×200). White arrows indicate few YFP+CD31+ ECs.  Endoderm Generates Endothelial Cells during Liver Development.  Gouon-Evans et al 2014.
FOXA2+ Cell Contribution to Fetal Liver ECs in Two Foxa2 Lineage-Tracing Mouse Models. (A–C) IF of fetal liver sections from E12.5 YFPpos embryos of Foxa2-iCre;YFP mice (×200). White arrows indicate the YFP+CD31+ ECs, and yellow arrowheads indicate the YFP-CD31+ hematopoietic cells. (D) Flow analyses from four E13.5 YFPpos fetal livers and one E13.5 YFPneg fetal liver of Foxa2-iCre;YFP mice. Numbers indicate the mean ± SD of the percentage of cell populations in each gate for four YFPpos embryos. (E) FOXA2 and YFP IF on E8.5 embryo section of Foxa2-CreTAM;YFP mice. Large image shows the tiling of a whole E8.5 embryo. The small image is a close-up of the foregut endoderm (×100). (F) IF of YFP and KDR at E8.5 of Foxa2-CreTAM;YFP mice (×200). White arrows indicate rare YFP+KDR+ cells. (G–I) IF for YFP and CD31 of E12.5 fetal liver sections from Foxa2-CreTAM;YFP mice (×200). White arrows indicate few YFP+CD31+ ECs. Endoderm Generates Endothelial Cells during Liver Development. Gouon-Evans et al 2014.

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