Fresh wind for old stem cell niches

Researchers at the Max Planck Institute and Münster University have discovered how to increase blood-forming stem cells

Blood vessels play a decisive role in the growth of bone tissue and in blood formation, or haematopoiesis. They not only supply oxygen and nutrients to the bone marrow, but also form so-called vascular niches. By means of certain signals they ensure that the blood-forming stem cells are preserved. If the number of niches increases, there is also a rise in the number of stem cells. In an ageing organism the quality of the stem cells deteriorates. Previously, however, it was not known how the niches change in this process. Researchers at the Max Planck Institute for Molecular Biomedicine, the Faculty of Medicine and the Cells-in-Motion (CiM) Cluster of Excellence have now found out how they can enhance the function of vascular stem cell niches in bone marrow and, as a result, increase the number of stem cells. They manipulated the endothelial cells, i.e. the cells which coat the blood vessels on the inside. These findings could later result in improved treatment of bone marrow diseases or in stem cell transplants being undertaken more individually. The study has been published in the renowned journal “Nature”.

Certain capillaries, so-called CD31-positive capillaries (red, arrowheads), and arteries (arrows) are formed after Notch activation in endothelial cells in ageing mice (right). They are missing, however, in control animals of the same age (left). Lines mark the outlines of the bones in cross-section, with cell nuclei coloured blue.
© MPI Münster - A. Kusumbe

The function of stem cells in bone marrow decreases with increasing age. This is due to the fact that the cells age and the function of the vascular niches deteriorates. A team of researchers headed by Dr. Anjali P. Kusumbe and Prof. Ralf H. Adams analysed these processes in mice. They examined the old bone marrow more closely and, in doing so, discovered that the network of blood vessels in ageing bones undergoes a fundamental change. The number of arteries and of certain capillaries, for example, decreases significantly. Moreover, around the blood cells there are fewer connective tissue cells, so-called mesenchymal cells. The production of signals for blood-forming stem cells also decreases.

At the same time the researchers found out how they could increase vascular niches and, as a result, the number of blood-forming stem cells. To this end they activated the endothelial cells in the innermost layer of the blood vessel wall. This was done by means of Notch signalling, through which neighbouring endothelial cells communicate with each another and coordinate their behaviour. The activation of Notch signalling leads to an increase in the number of special capillaries, to the formation of small arteries and to an increase in mesenchymal connective tissue cells around the blood vessels. At the same time the production of signals for the blood-forming stem cells in the bone marrow increases. “Only a combination of all these factors together produces new stem cell niches,” says Ralf Adams. “By contrast, without new arteries and mesenchymal cells no vascular niches can be formed.” He and his fellow researchers thus decoded a highly complex system.

Dr. Anjali P. Kusumbe is the first author of the study which has been published in the journal "Nature".
© MPI Münster

The researchers were also able to increase the number of vascular stem cell niches in the endothelium of ageing mice – by activating the Notch signalling and thus manipulating the endothelium. In doing so they were not, however, able to reverse the ageing process in the blood-forming stem cells. “But the manipulation of the endothelium and the associated increase in stem cell niches could be significant for the treatment of bone marrow diseases or in therapeutic stem cell transplants,” says Ralf Adams, looking ahead into the future. More specifically, this would affect older people, for example, or patients who show a less than satisfactory reaction to a stem cell transplant.

The study was the result of international collaboration between various research institutes in Germany, Israel and Sweden. In Münster, the Max Planck Institute for Molecular Biomedicine, the Faculty of Medicine and the Cells-in-Motion Cluster of Excellence at Münster University were all involved. Ralf Adams heads one of around 80 research groups within the Cluster.

Original publication:
Anjali P. Kusumbe, Saravana K. Ramasamy, Tomer Itkin, Maarja Andaloussi Mäe, Urs H. Langen, Christer Betsholtz, Tsvee Lapidot, Ralf H. Adams (2016), Age-dependent modulation of vascular niches for haematopoietic stem cells. Nature, DOI: 10.1038/nature17638. Abstract