Blood stem cell self-renewal dependent on surroundings

November 03, 2015

Stem cells have two important capabilities: they can develop into a wide range of cell types and simultaneously renew themselves, creating fresh stem cells. Using a model of the blood forming (hematopoietic) system, researchers at the Technical University of Munich (TUM) have now been able to precisely determine, which signaling pathways play an essential role in the self-renewal of blood stem cells. A particularly decisive role in this process is the interactive communication with surrounding tissue cells in the bone marrow.

Our blood is generated by blood-forming (hematopoietic) stem cells (HSCs) in the bone marrow. In conjunction with bone marrow tissue cells, these HSCs form a microenvironment known as a niche. As long as the body is healthy, the HSCs remain in "standby" mode. But if an accident leads to substantial blood loss, for instance, or the defense against a pathogen requires more blood cells in the course of an infection, the stem cells are activated.

In response, the entire blood cell formation system switches from standby into a state of alert. The activated stem cells generate new blood cells of every type to counteract the blood loss or combat the pathogen. At the same time, self-renewal keeps the stem cell pool replenished.

This switch is accompanied by a complex communication process between the stem cells and tissue cells - an area that had not previously been examined in any depth. "In our study, we set out to establish which tissue signals are important to stem cell maintenance and functionality, and which HSC signals influence the microenvironment," explains Prof. Robert Oostendorp from TUM's university hospital, Klinikum rechts der Isar, where he works at the III. Medizinische Klinik led by Prof. Christian Peschel. Together with team members Dr. Rouzanna Istvánffy and Dr. Baiba Vilne, Oostendorp used mixed cultures of tissue and stem cells to investigate how the two cell types interact.

Tissue cells trigger stem cell renewal

To unravel the complex signaling pathway map, the scientists used their own findings from the analysis of factors regulated up or down in the interplay between tissue and stem cells, linking them with the signaling pathways described in existing literature. They then consolidated this information within a bioinformatics computer model. To achieve this, the researchers collaborated with a group led by Prof. Hans-Werner Mewes, TUM's Professor of Genome-Oriented Bioinformatics. Finally, the team conducted extensive cell experiments to confirm the computer-generated signaling pathway model.

"The outcome was very interesting indeed: the entire system operates in a feedback loop," reveals Oostendorp. Summing up the results, he continues: "In alert mode, the stem cells first influence the behavior of the tissue cells - which, in turn, impact on the stem cells, triggering the self-renewal step."

Important ramifications also for leukemia treatment

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 connective tissue growth factor (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.

"Our findings could prove significant in treating leukemia. In this condition, the stem cells are hyperactive and their division is unchecked," describes 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, it would be important to integrate the surrounding cells in therapeutic approaches too, since they exert a strong influence on stem cell division," the scientist confirms.

R. Istvánffy, B. Vilne, C. Schreck, F. Ruf, C. Pagel, S. Grziwok, L. Henkel, O. Prazeres da Costa,
J. Berndt, V. Stümpflen, K. S. Götze, M. Schiemann, C. Peschel, H.-W. Mewes, R.A.J. Oostendorp, Stroma-derived connective tissue growth factor (CTGF) maintains cell cycle progression and repopulation activity of hematopoietic stem cells in vitro, Stem Cell Reports, October 29, 2015.
DOI: 10.1016/j.stemcr.2015.09.018


Prof. Robert Oostendorp
Klinikum rechts der Isar, Technical University of Munich
III. Medizinische Klinik
Phone: +49 (0)89 4140-6056

Technical University of Munich (TUM)

Related Stem Cells Articles from Brightsurf:

SUTD researchers create heart cells from stem cells using 3D printing
SUTD researchers 3D printed a micro-scaled physical device to demonstrate a new level of control in the directed differentiation of stem cells, enhancing the production of cardiomyocytes.

More selective elimination of leukemia stem cells and blood stem cells
Hematopoietic stem cells from a healthy donor can help patients suffering from acute leukemia.

Computer simulations visualize how DNA is recognized to convert cells into stem cells
Researchers of the Hubrecht Institute (KNAW - The Netherlands) and the Max Planck Institute in Münster (Germany) have revealed how an essential protein helps to activate genomic DNA during the conversion of regular adult human cells into stem cells.

First events in stem cells becoming specialized cells needed for organ development
Cell biologists at the University of Toronto shed light on the very first step stem cells go through to turn into the specialized cells that make up organs.

Surprising research result: All immature cells can develop into stem cells
New sensational study conducted at the University of Copenhagen disproves traditional knowledge of stem cell development.

The development of brain stem cells into new nerve cells and why this can lead to cancer
Stem cells are true Jacks-of-all-trades of our bodies, as they can turn into the many different cell types of all organs.

Healthy blood stem cells have as many DNA mutations as leukemic cells
Researchers from the Princess Máxima Center for Pediatric Oncology have shown that the number of mutations in healthy and leukemic blood stem cells does not differ.

New method grows brain cells from stem cells quickly and efficiently
Researchers at Lund University in Sweden have developed a faster method to generate functional brain cells, called astrocytes, from embryonic stem cells.

NUS researchers confine mature cells to turn them into stem cells
Recent research led by Professor G.V. Shivashankar of the Mechanobiology Institute at the National University of Singapore and the FIRC Institute of Molecular Oncology in Italy, has revealed that mature cells can be reprogrammed into re-deployable stem cells without direct genetic modification -- by confining them to a defined geometric space for an extended period of time.

Researchers develop a new method for turning skin cells into pluripotent stem cells
Researchers at the University of Helsinki, Finland, and Karolinska Institutet, Sweden, have for the first time succeeded in converting human skin cells into pluripotent stem cells by activating the cell's own genes.

Read More: Stem Cells News and Stem Cells Current Events is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to