Neural Crossroads in the Hematopoietic Stem Cell Niche

Abstract

The hematopoietic stem cell (HSC) niche supports steady-state hematopoiesis and responds to changing needs during stress and disease. The nervous system is an important regulator of the niche, and its influence is established early in development when stem cells are specified. Most research has focused on direct innervation of the niche, however recent findings show there are different modes of neural control, including globally by the central nervous system (CNS) and hormone release, locally by neural crest-derived mesenchymal stem cells, and intrinsically by hematopoietic cells that express neural receptors and neurotransmitters. Dysregulation between neural and hematopoietic systems can contribute to disease, however new therapeutic opportunities may be found among neuroregulator drugs repurposed to support hematopoiesis.

Keywords: Hematopoietic stem cells; hematopoiesis; nervous system; neural; neuronal; stem cell niche.

Figure 1. Innervation of the Bone Marrow Niche.

Most sympathetic (TH+) nerves reach arterioles and their surrounding pericytes. These pericytes (PAA cells/Nestin-GFP^bright/NG2+/α-SMA+) ensheath arterioles and nerves. Pericytes are linked by connexin-43 (Cx43+) gap junctions (arrowheads) that have been proposed as conduits for neuronal signals that spread through an interconnected syncytial network (dashed arrows). Schwann cells (GFAP+) are also associated with arterioles. The arteriolar niche is rich with fine collagen fibers. Neurons extend into the bone where they contact osteoblasts and osteocytes. There is minimal innervation of sinusoidal vessels that are associated with reticular mesenchymal stromal cells (CAR cells/Nestin GFP^dim/Cxcl12+/Lepr+/Scf+). CAR, CXCL12-abundant reticular; GFAP, glial fibrillary acidic protein; HSC, hematopoietic stem cell; PAA, periarterial adventitial; TH, tyrosine hydroxylase.

Figure 2.. Electron Microscopy Studies Show Pericyte-like PAA Cells Wrapping Arterioles

(A) Transmission electron microscopy of arterioles (a), capillaries, and periarterial adventitial (PAA)cells in the bone marrow of amouse femur. Transverse section of an arteriole near a sinus (S) and central vein (CV). Arrowheads indicate the thin cytoplasmic processes of PAA cells surrounding the arteriole and separating it from hematopoietic parenchyma. One nerve (N) contains 5 myelinated axons and 17 unmyelinated axons and is bounded by the layers of perineurium. (B) High-power view of a zonula adherens-type junction between PAA cells [dashed red box in (A)]. (C) Three-dimensional configuration of PAA cells as observed by scanning electron microscopy. Transverse fracture across the long axis of an arteriole near the central vein and sinus. The thin, veil-like cytoplasmic processes of the PAA cells (arrows) surround the smooth muscle cells of the arteriole. Between them, fine filaments of collagen fibers (arrowheads) are present. The PAA cells also cover a nerve in a sheath-like configuration. Images are adapted, with permission from, Yamazaki and Allen [16].

Figure 3. Neural Crest Derivatives are Found Adjacent to the Site of HSC Emergence in the Dorsal Aorta of Mouse and Zebrafish.

(A,B) Zebrafish transgenic reporter showing neural crest (red) and endothelium (green). (A) Cells derived from the neural crest contact the ventral wall of the dorsal aorta. Transverse confocal section of midtrunk region at 24 hours postfertilization (hpf); dorsal up, ventral down; white arrowhead indicates pigment cell lineages migrating ventrolaterally. Scale bars: 50 microns. (B) Zoomed region shown in white box in (A) with yellow arrowhead indicating a neural crest cell between the dorsal aorta (da) and posterior cardinal vein (pcv). (C) E11.5 mouse embryo showing sympathoadrenal neural crest-derived cells (green) adjacent to the ventral wall of the dorsal aorta (red). Lateral confocal Z-stack image (anterior left, posterior right). no, Notochord; nt, neural tube; sg, sympathetic ganglia. Images are adapted with permission from: (A,B) Damm and Clements [10]; (C) Lumb and Schwarz [75].