Abstract
Dormancy of hematopoietic stem cells and formation of progenitors are directed by signals that come from the bone marrow microenvironment. Considerable knowledge has been gained on the murine hematopoietic stem cell microenvironment, while less so on the murine progenitor microenvironment and even less so on these microenvironments in humans. Characterization of these microenvironments is decisive for understanding hematopoiesis and finding new treatment modalities against bone marrow malignancies in the clinic. However, it is equally challenging, because hematopoietic stem cells are difficult to detect in the complex bone marrow landscape. In the present study we are characterizing the human hematopoietic stem cell and progenitor microenvironment. We obtained three adjacent bone marrow sections from ten healthy volunteers. One was used to identify a population of CD34+/CD38- “hematopoietic stem cells and multipotent progenitors” and a population of CD34+/CD38+ “progenitors” based on immunofluorescence pattern/intensity and cellular morphology. The other two were immunostained respectively for CD34/CD56 and for CD34/SMA. Using the combined information we performed a non-computer-assisted quantification of nine bone marrow components (adipocytes, megakaryocytes, bone surfaces, four different vessel types (arteries, capillaries, sinusoids and collecting sinuses), other “hematopoietic stem cells and multipotent progenitors” and other “progenitors”) within 30 μm of “hematopoietic stem cells and multipotent progenitors”, “progenitors”, and “random cell profiles”. We show that the microenvironment of the “hematopoietic stem cells and multipotent progenitors” is significantly enriched in sinusoids and megakaryocytes, while the microenvironment of the “progenitors” is significantly enriched in capillaries, other “progenitors”, bone surfaces and arteries.
Highlights
In 1978, Schofield [1] hypothesized that hematopoietic stem cells (HSCs) are regulated by cells in the microenvironment
The available studies performed on bone marrow (BM) biopsies point in different directions, with one study indicating that the majority of hematopoietic stem and progenitor cells (HSPCs) are positioned close to sinusoids and mesenchymal stromal cells (MSCs) [8], while other studies indicate that HSPCs are mainly positioned close to bone surfaces [3,9,16]
We show that the microenvironment of the HSCs/multipotent progenitor (MPP) is significantly enriched in sinusoids and megakaryocytes, while the microenvironment of the progenitors is significantly enriched in capillaries, other progenitors, bone surfaces and arteries
Summary
In 1978, Schofield [1] hypothesized that hematopoietic stem cells (HSCs) are regulated by cells in the microenvironment. Our ability to develop new treatment modalities targeted against the malignant microenvironment in humans, implies specific knowledge of the human microenvironment. Exactly this knowledge is sparse, since most human stem cell studies are performed on aspirated cells using flow cytometry. There is a considerable volume of knowledge in mice This knowledge strongly supports that the major HSC regulatory BM components are the MSCs and the sinusoids [2,6,7,14,15], whereas a subset of the progenitors are positioned close to bone surfaces [7]. Associated to the sinusoids are the megakaryocytes that have been shown to be a part of the HSC niche in mice [4,17], while we are still lacking specific knowledge about this in humans
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