According to a bioinformatics model and supporting cell experiments, a functioning, responsive hematopoietic niche depends on specific signaling pathways between blood stem cells and surrounding tissue cells. This image shows a stroma cell of the bone marrow of a mouse secreting connective tissue growth factor (red). The cell’s nucleus is stained in blue. [Rouzanna Istvanffy/TUM]
According to a bioinformatics model and supporting cell experiments, a functioning, responsive hematopoietic niche depends on specific signaling pathways between blood stem cells and surrounding tissue cells. This image shows a stroma cell of the bone marrow of a mouse secreting connective tissue growth factor (red). The cell’s nucleus is stained in blue. [Rouzanna Istvanffy/TUM]

From the depths of the hematopoietic niche, blood cells emerge to sustain life. But what sustains the flow of blood cells, or accounts for the occasional surge? The shallow answer is, of course, blood stem cells. A deeper inquiry, however, might consider how blood stem cells are able to rise to a wide range of cell types while simultaneously renewing themselves. Even deeper, there is the question of how blood stem cells respond to changing circumstances, such as injury and disease, by switching from “standby” to “alert” mode, countering blood loss or fighting pathogens.

Penetrating these depths, researchers at the Technical University of Munich (TUM) investigated the complex communication process that takes place within the hematopoietic niche, the back-and-forth signaling that occurs between the stem cells and the surrounding tissue cells in the bone marrow. Essentially, the researchers took it upon themselves to explore the signaling space of the bone marrow microenvironment, a still-obscure region.

“In our study, we set out to establish which tissue signals are important to stem cell maintenance and functionality, and which hematopoietic stem cell signals influence the microenvironment,” explained TUM’s Prof. Robert Oostendorp. According to Prof. Oostendorp, his team started mixing cultures of tissue and stem cells to investigate how the two cell types interact. Basically, they determined which factors were up-regulated or down-regulated, and how various factor fluctuations correlated with signaling pathways described in the literature.

Ultimately, the TUM researchers consolidated their findings in a bioinformatics computer model, and the outcome, noted Prof. Oostendorp, was “very interesting indeed.” The entire system was found to operate in a feedback loop. “In alert mode,” Prof. Oostendorp explained, “the stem cells first influence the behavior of the tissue cells—which, in turn, impact on the stem cells, triggering the self-renewal step.”

Details of this work appeared October 29 in the journal Stem Cell Reports, in an article entitled, “Stroma-Derived Connective Tissue Growth Factor Maintains Cell Cycle Progression and Repopulation Activity of Hematopoietic Stem Cells In Vitro.”

“Our analyses clearly show that stromal cells react to the presence of Lineage-negative (Lin−) SCA-1+ KIT+ (LSK) cells, which are enriched for HSCs. These studies indicate that LSK cells induce expression of connective tissue growth factor (CTGF) in stromal cells,” wrote the authors. “We show that CTGF is required particularly for maintenance of long-term myeloid repopulating HSC activity in culture by controlling the cell-division behavior of HSCs. Biochemical confirmation studies of a CTGF signaling network model LSK show that stromal CTGF regulates G0/G1 transition of in LSK cells by concerted action on transforming growth factor and WNT signaling pathways.”

The team's findings paint a clear picture: in alert mode, the stem cells emit signaling substances, which in turn induce tissue cells to release the CTGF messenger. This is essential to maintain the stem cells through self-renewal. In the absence of CTGF, the stem cells age and cannot replenish.

The coordination between the stem cells and the tissue cells in the hematopoietic niche could be said, with apologies to James Fenimore Cooper, to result in a flow that cannot be frozen by adversity, as the water that flows from the spring cannot congeal in winter. Yet sometimes a flow can turn into a flood.

“Our findings could prove significant in treating leukemia. In this condition, the stem cells are hyperactive and their division is unchecked,” asserted Prof. Oostendorp. “Leukemic blood cells are in a constant state of alert, so we would expect a similar interplay with the tissue cells.” To date, however, the focus here has been limited to stem cells as the actual source of the defect. “Given what we know now about feedback loops,” Prof. Oostendorp elaborated, “it would be important to integrate the surrounding cells in therapeutic approaches too, since they exert a strong influence on stem cell division.”








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