New approach to improve bone transplantation

Findings of a new study appearing in the Journal of Clinical Investigation may lead to strategies to improve bone transplantation.

Hematopoietic stem cells (HSCs) in the bone marrow have a capacity of multi-potency and self-renewal. Multi-potency refers to the ability to differentiate into all functional blood cells, including both myeloid cells and lymphoid cells. The process in which HSCs give rise to blood cells is called hematopoiesis. HSCs mostly stay in a quiescence state under normal conditions. But these cells promptly switch to a proliferative state after bone marrow injury, bone transplantation, and systemic infection or inflammation.

Recently, a multinational group of researchers has found a protein that regulates the balance of quiescence, self-renewal, and differentiation of HSCs. The protein, called Del-1, may be manipulated to facilitate bone transplantation and to treat diseases that affect the bone marrow.

The study revealed that Del-1 is expressed by several types of cells in the HSC niche. Moreover, Del-1 is a secreted extracellular matrix protein. Since Del-1 is soluble, it is relatively easy to find ways to modulate it.

To better understand the function of Del-1, the researchers carried out experiments in mice. They found that Del-1 promotes the proliferation and differentiation of HSCs toward myeloid cells, such as macrophages and neutrophils. Del-1-deficient mice exhibited reduced HSC proliferation in comparison with the control mice.

Hematopoietic cell transplantation experiments showed that Del-1 helps the transplanted cells to engraft in the recipient mice. Moreover, Del-1 promotes the differentiation of the transplanted cells into myeloid cells.

Subsequent experiments identified a mechanism about how Del-1 works. The researchers found that Del-1 interacts with β3 integrin on hematopoietic progenitors. The Del-1/β3 integrin interaction facilitates HSC proliferation and differentiation into myeloid cells after transplantation.

Collectively, the data establish a regulatory role of Del-1 in the bone marrow. Both Del-1 and β3 integrin are potential targets to improve bone transplantation.

Besides, the findings may have implications for the treatment of many human diseases. For example, febrile neutropenia, a complication of chemotherapy and a condition associated with bone transplantation, involves an abnormally low number of neutrophil granulocytes. Del-1 has a role in boosting the production of myeloid cells such as neutrophils. Therefore, manipulation of Del-1 may be a strategy to treating febrile neutropenia. This hypothesis warrants further research.

The study is co-led by Dr. George Hajishengallis from the University of Pennsylvania in the USA and Dr. Triantafyllos Chavakis from Technische Universität Dresden in Germany.
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