U.S. Department of Health and Human Services

Blood Cell Formation and Regeneration

 

Scientists have recently determined that two biologic pathways, the bone morphogenetic protein (BMP) and Wnt signaling pathways, play a dynamic role in blood cell (hematopoietic) regeneration and maturation (differentiation). Following an insult or injury to the blood system, such as rapid blood loss due to a serious injury, the regenerative process stimulates rapid expansion of hematopoietic stem cells followed by differentiation of these cells into red blood cells and other major blood cell types. Both BMP and Wnt signaling pathways contribute to the initial formation of the hematopoietic system during development, but it was not known whether these pathways are also involved in hematopoietic regeneration and differentiation after injury during adulthood. 

To evaluate whether BMP and/or Wnt signaling pathways contribute to blood cell regeneration, scientists performed experiments on zebrafish, a model organism. They subjected adult zebrafish to a sub-lethal dose of radiation to destroy their existing blood cells. They then looked for signs of blood cell regeneration by characterizing blood cell populations from zebrafish kidney marrow, which is considered the organ responsible for production of all major blood cell types, analogous to the mammalian bone marrow. The regeneration of blood cells following irradiation of the fish was shown to depend on the activation of both the BMP and Wnt signaling pathways. 

The researchers next gained insight into how these signaling pathways promote regeneration of different types of blood cells. Drawing upon previous findings that the BMP and Wnt pathways act by turning genes on or off, the scientists sought to identify other factors involved in this process. Two gene-regulating factors, SMAD1, a member of the BMP signaling family, and TCF7L2, a member of the Wnt signaling family, were found to be associated with genes that play a role in the production of blood cells. Furthermore, when the researchers examined red blood cells grown in the laboratory, these factors were found to be bound to DNA in close proximity to known “master regulators” GATA1 and GATA2, which are important for directing gene regulation in a particular progenitor cell so that it becomes a red blood cell. Interestingly and importantly, in a white blood cell line, SMAD1 and TCF7L2 were not found to be associated with red blood cell genes in the zebrafish DNA, but rather were associated with white blood cell genes. In these cells, SMAD1 and TCF7L2 were both in close proximity to a different master regulator, C/EBPα—important for directing a particular progenitor cell to become a white blood cell. 

This study identifies signaling pathways and factors associated with different master regulators of genes, which direct the regeneration and differentiation of distinct blood cell types in adults following injury.

Trompouki E, Bowman TV, Lawton LN, et al. Lineage regulators direct BMP and Wnt pathways to cell-specific programs during differentiation and regeneration. Cell 147: 77-589, 2011.