Shedding Light on Migration of the Hematopoietic Niche Into Bone

Like many of us, when I sit down with a patient to review their diagnosis, I start with a cartoon drawing of a bone. Often, as I have sketched out the function of stem cells and given a short lesson in hematopoiesis and blood-cell pathology, it’s occurred to me how much we don’t know about this process.

A recent, fascinating article by Dr. Friedrich Kapp and colleagues points to the resolution of a question that has troubled me for many years. Why does bone marrow have to be located in the middle of bones?

Hemopoietic stem cells are always on the move. During human development, they migrate from the aorta-gonad-mesonephros region to the fetal liver and then to the bone marrow around the time of birth. Over the course of evolution, they moved from the kidney marrow in fish into the bone marrow in land animals. So what are the selective forces that drove this pattern?

This is the question that lies at the heart of this recent article published in Nature. The authors noted that the hemopoietic stem and progenitor cells (HSPC) in the kidney marrow of zebrafish larvae were covered by a mantle of melanocytes. The authors were aware that in 1979, Dr. Edwin Cooper suggested that HSPCs were located in the bone marrow of land animals as this provided protection from ionizing radiation that could damage the DNA of these critical stem cells.¹  However, ionizing radiation, which can strip electrons from atoms and includes gamma rays and X rays, is mostly filtered out by sunlight, and so the team wondered if the melanocytes might act to protect aquatic HSPCs from nonionizing radiation such as ultraviolet light. Indeed, zebrafish mostly swim in shallow water around paddy fields, and as such, are exposed to intense sunlight in their natural habitat.

The investigators then generated a genetic knockout of a transcription factor (mitfa) that controls melanocyte differentiation and created zebrafish that lacked melanocytes. Importantly, this did not entirely disrupt the stem cell niche such that normal numbers of stem cells and blood cells were seen under resting laboratory light conditions. However, the team then went on to apply the challenge of ultraviolet light (UVB; 280-315 nm), giving a dose equivalent to that which would create sunburn in a fair-skinned person. The wild-type larvae tolerated UVB well, but in the melanocyte-deficient animals, there was an increase in UV-induced DNA damage and a decrease in both HSPC number and blood cell production. As further evidence for the protective effect of the melanocyte cover, similar findings were observed when melanin production was inactivated. A further experimental innovation was to anaesthetize the larvae such that they rolled upside down on their backs and the HSPCs were directly exposed to UVB challenge. In this situation, the damaging effects of UVB were seen even in the wild-type animals, indicating that the anatomical orientation of the melanocytes is critical.

Comparative studies in many other fish also revealed melanocytes covering the hematopoietic kidney marrow. In contrast, the HSPCs in all animals found on land are located within the bone marrow. The final beautiful coda in the report was the demonstration that tadpoles of frogs have melanocytes around HSPCs in the kidney marrow, but that the HSPCs move to the bone marrow at the time that the limbs develop. The presence of the cortical bone was indeed then shown to provide strong protection against UVB-induced damage.