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Researchers identify two new genes involved in the immune system.

Researchers from the UCLA have shown that two genes not previously known to be involved with the immune system play a crucial role in how progenitor stem cells are activated to fight infection.  This discovery lays the groundwork for a better understanding of the role progenitor cells can play in immune system response and could lead to the development of more effective therapies for a wide range of diseases.  The two-year study is published in the journal Current Biology.

Progenitor cells are the link between stem cells and fully differentiated cells of the blood system, tissues and organs. This maturation process, known as differentiation, is determined in part by the original environment that the progenitor cell came from, called the niche. Many of these progenitors are maintained in a quiescent state or standby mode and are ready to differentiate in response to immune challenges such as stress, infection or disease.

The team built upon the lab’s previous research that utilized the blood system of the fruit fly species Drosophila to show that a specific set of signals must be received by progenitor cells to activate their differentiation into cells that can work to fight infection after injury. The researchers focused on two genes previously identified in stem cells but not in the blood system, named Yorkie and Scalloped, and discovered that they are required in a newly characterized cell type called a lineage specifying cell. These cells then essentially work as a switch, sending the required signal to progenitor cells.

The researchers further discovered that when the progenitor cells did not receive the required signal, the fly would not make the mature cells required to fight infection. This indicates that the ability of the blood system to fight outside infection and other pathogens is directly related to the signals sent by this new cell type.

The beauty of this study is that the medical community now has a system in which they can investigate how a signaling cell uses these two genes, Yorkie and Scalloped, which have never before been shown in blood, to direct specific cells to be made.  It can help to eventually answer the question of how the body knows how to make specific cell types that can fight infection.

The researchers said that they hope future studies will examine these genes beyond Drosophila and extend to mammalian models, and that the system will be used by the research community to study the role of the genes Yorkie and Scalloped in different niche environments.

At a biochemical level, there is a lot of commonality between the molecular machinery in Drosophila and that in mice and humans.  This study can further shared understanding in the medical community of how the microenvironment can regulate the differentiation and fate of a progenitor or stem cell.

The team state that looking at the functionality of these genes and their effect on the immune response has great potential for accelerating the development of new targeted therapies.

Source:  The UCLA Health System

 

Cellular microenvironments established by the spatial and temporal expression of specific signaling molecules are critical for both the maintenance and lineage-specific differentiation of progenitor cells. In Drosophila, a population of hematopoietic progenitors, or prohemocytes, within the larval lymph gland gives rise to three mature cell types: plasmatocytes, lamellocytes, and crystal cells. Removal of the secreted signaling molecules Hedgehog and PVF1 from the posterior signaling center, which acts as a niche, leads to a loss of progenitors and complete differentiation of the lymph gland. Here, we characterize a novel population of signaling cells within the lymph gland, distinct from the PSC, that are required for lineage-specific differentiation of crystal cells. We provide evidence that Yorkie and Scalloped, the Drosophila homologs of YAP and TEAD, are required in lineage-specifying cells to regulate expression of Serrate, the Notch ligand responsible for the initiation of the crystal cell differentiation program. Genetic manipulation of yorkie and scalloped in the lymph gland specifically alters Serrate expression and crystal cell differentiation. Furthermore, Serrate expression in lineage-specifying cells is eliminated in the lymph gland upon the immune response induced by wasp parasitization to ensure the proper differentiation of lamellocytes at the expense of crystal cells. These findings expand the roles for Yorkie/Scalloped beyond growth to encompass specific cell-fate determination in the context of blood development. Similar regulatory functions may extend to their homologs in vertebrate progenitor cell niches that are required for specifying cell fate.  Yorkie and Scalloped Signaling Regulates Notch-Dependent Lineage Specification during Drosophila Hematopoiesis.  Martinez-Agosto et al 2014.
Cellular microenvironments established by the spatial and temporal expression of specific signaling molecules are critical for both the maintenance and lineage-specific differentiation of progenitor cells. In Drosophila, a population of hematopoietic progenitors, or prohemocytes, within the larval lymph gland gives rise to three mature cell types: plasmatocytes, lamellocytes, and crystal cells. Removal of the secreted signaling molecules Hedgehog and PVF1 from the posterior signaling center, which acts as a niche, leads to a loss of progenitors and complete differentiation of the lymph gland. Here, we characterize a novel population of signaling cells within the lymph gland, distinct from the PSC, that are required for lineage-specific differentiation of crystal cells. We provide evidence that Yorkie and Scalloped, the Drosophila homologs of YAP and TEAD, are required in lineage-specifying cells to regulate expression of Serrate, the Notch ligand responsible for the initiation of the crystal cell differentiation program. Genetic manipulation of yorkie and scalloped in the lymph gland specifically alters Serrate expression and crystal cell differentiation. Furthermore, Serrate expression in lineage-specifying cells is eliminated in the lymph gland upon the immune response induced by wasp parasitization to ensure the proper differentiation of lamellocytes at the expense of crystal cells. These findings expand the roles for Yorkie/Scalloped beyond growth to encompass specific cell-fate determination in the context of blood development. Similar regulatory functions may extend to their homologs in vertebrate progenitor cell niches that are required for specifying cell fate. Yorkie and Scalloped Signaling Regulates Notch-Dependent Lineage Specification during Drosophila Hematopoiesis. Martinez-Agosto et al 2014.

 

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