Neural regulation of hematopoiesis, inflammation, and cancer

Abstract

Although the function of the autonomic nervous system (ANS) in mediating the flight-or-fight response was recognized decades ago, the crucial role of peripheral innervation in regulating cell behavior and response to the microenvironment has only recently emerged. In the hematopoietic system, the ANS regulates stem cell niche homeostasis and regeneration and fine-tunes the inflammatory response. Additionally, emerging data suggest that cancer cells take advantage of innervating neural circuitry to promote their progression. These new discoveries outline the need to redesign therapeutic strategies to target this underappreciated stromal constituent. Here, we review the importance of neural signaling in hematopoietic homeostasis, inflammation, and cancer.

Figure 1. Autonomic neural circuits

The autonomous nervous system (ANS) is comprised of a sympathetic division (right), emerging from the thoraco-lumbal spinal cord, and a parasympathetic division (left) derived from cranial nerves and the sacral spinal cord. The ANS requires preganglionic and postganglionic neurons, forming synapses in the autonomic ganglion to connect the central nervous system to its targets. (I) Sympathetic nerve fibers in the bone marrow locally release neurotransmitters that activate adrenergic receptors expressed on niche cells and thus regulate the maintenance and retention of hematopoietic stem and progenitor cells in the bone marrow. (II) Neural circuits comprised of cholinergic and adrenergic neurons, splenic T cells and splenic macrophages regulate the innate immune response. Activation of the HPA axis may also counter-balance inflammation through glucocorticoids released from the adrenal cortex.

Figure 2. Autonomic signals modulate steady-state hematopoiesis

Different stromal cell types, including nestin-expressing perivascular cells, endothelial cells and CAR cells, regulate HSC maintenance. Although osteoblasts are dispensable for HSC maintenance, osteolineage cells may contribute to HSC regulation and for lymphoid progenitor cells maintenance. The neuronal components of the HSC niche comprise peripheral sympathetic neurons and non-myelinating Schwann cells that maintain HSC dormancy through activation of the TGF-β/SMAD signaling. Circadian noradrenaline secretion from sympathetic nerves leads to circadian expression of CXCL12 by nestin⁺ MSPCs, resulting in rhythmic release of HSCs to the periphery. The adrenergic signals in this case are mediated through the β3-adrenergic receptors (Adrβ3). Quiescent HSCs are located in close proximity to arteriolar blood vessels, ensheathed with sympathetic nerve fibers and Nestin^high NG2⁺ pericytes, however, upon activation, relocate near the Nestin^low LepR-expressing perisinusoidal area. Similar to MSPCs, sympathetic signals also regulate bone formation, via β2-adrenergic receptor (Adrβ2) signaling in osteoblasts.

Figure 3. Sympathetic denervation compromises hematopoietic regeneration

Sympathetic neuropathy of the bone marrow damages the HSCs niche by driving proliferation of nestin⁺ MSPCs and endothelial cells. SNS injury to the bone marrow disrupts HSC and progenitor mobilization, and upon damaging evens such as chemotherapy or radiation, the niche size decreases and fails to support hematopoiesis.

Figure 4. Sympathetic neuropathy promotes hematopoietic malignancy

(A) AML induces sympathetic neuropathy of the leukemic niche. Development of MLL-AF9-driven AML disrupts SNS nerves within the leukemic bone marrow niche. The SNS neuropathy is accompanied with expansion of nestin⁺ MSPCs primed for osteoblastic differentiation at the expense of HSC-maintaining Nestin^high NG2⁺ pericytes. In addition, AML is also associated with increased vascular density. The adrenergic signals regulating LSCs are transduced by the β2-adrenergic receptor (Adrβ2) expressed on stromal cells in leukemic bone marrow. (B) Bone marrow neuropathy is essential for the development of MPN. Sympathetic nerve fibers, non-myelinating Schwann cells and Nestin⁺ MSPCs are consistently reduced in MPN bone marrow driven by JAK2(V617F) mutations in HSCs. In contrast to AML, the reduction in Nestin⁺ MSPCs is not due to differentiation, but neural damage coinciding with Schwann cell and Nestin⁺ MSPCs apoptosis triggered by IL-1β production by mutant HSCs. Treatment with β3-adrenergic agonist blocked MPN progression, suggesting that the adrenergic signals were transduced via the β3-adrenergic receptor (Adrβ3) present on MPN bone marrow stromal cells.

Figure 5. Autonomic nerves are an active component of the tumor microenvironment

Tumor microenvironment is heterogeneous and composed of fibroblasts, blood vessels, nerves fibers, macrophages and other immune cells that actively interact with tumor cells to regulate cancer progression. Under stress situations, nerve fibers recruited within and around the tumor release catecholamines in the tumor stroma. Both tumor cells and stromal cells express β2-adrenergic receptors (Adrβ2), and respond to norepinephrine which promotes tumor growth. Pericytes, within the tumor microenvironment, express dopamine receptor type 2 (DR2) and respond to dopamine which regulates angiogenesis. Moreover, tumor cells invade autonomic nerves (perineural invasion) in several cancer types causing pain and may facilitate systemic spreading.

Figure 6. Metastases at different sites are regulated by autonomic nerve signals

Both branches of the autonomic nervous system can promote metastatic spread of solid tumors. (Left) Lung metastases are increased in mice harboring breast tumor xenografts when subjected to chronic stress. Stress-mediated signals stimulate the recruitment of CD11b⁺ F4/80⁺ macrophages in breast tumor orthotopic xenografts. These macrophages express β2-adrenergic receptors and enhance the lung metastatic capacity of tumor cells without affecting primary tumor growth. (Right) Muscarinic receptor 1 (Chrm1) expressed in the tumor stroma promotes prostate tumor cell invasion and metastasis to lymph nodes and distant organs. However, it is not yet known which cell of the stroma is targeted by parasympathetic signals.