Beneath the hard surfaces of the bone lies the source of all blood cells: the bone marrow (BM) [1]. When compared with other mammalian organs, the hematopoietic tissue is remarkably efficient at its task, ensuring a daily production of blood cells in incredible numbers from a limited pool of undifferentiated cells called hematopoietic stem cells (HSCs) [1], [2]. These cells undergo a tightly-knit process named hematopoiesis, where self-renewal and differentiation remain in balance to fulfill the high demand for mature blood cells while also ensuring that HSCs maintain their stem cell properties [1]. To achieve this balance between renewal and differentiation, the BM boasts a complex platform for cellular interactions called the BM microenvironment or “niche” [1].

This specialized niche concept was first proposed by Schofield in 1978 [3]. As the field advanced, the BM niche became widely recognized as a major influencer behind the function of HSCs and their progenies. Yet despite said advancements, many mechanisms behind the functioning of the hematopoietic niche remain elusive.

Semaphorins (SEMAs), a large family of proteins first identified in the nervous system as regulators of axonal guidance [4], have been described as having diverse tasks that expand their functionality beyond their original discovery. As such, their participation in physiological and pathological processes is a subject that has been extensively described in the literature [5], [6]. Establishing a relationship between these proteins and hematopoiesis, however, remains largely uncharted territory.

In this review, we discuss the current knowledge on the BM niche while also proposing links between said niche and mammalian SEMAs. We divide the BM structure in endosteal, perivascular, and endothelial niches while exploring how they could interact with SEMAs. We also provide insight into possible new pathways of hematopoietic regulation, which is the basis behind understanding blood diseases. A visual representation of the three main BM niche representatives can be found in Fig. 1.