Neuroimmune/Hematopoietic Axis with Distinct Regulation by the High-Mobility Group Box 1 in Association with Tachykinin Peptides

Abstract

Hematopoiesis is tightly regulated by the bone marrow (BM) niche. The niche is robust, allowing for the return of hematopoietic homeostasis after insults such as infection. Hematopoiesis is partly regulated by soluble factors, such as neuropeptides, substance P (SP), and neurokinin A (NK-A), which mediate hematopoietic stimulation and inhibition, respectively. SP and NK-A are derived from the Tac1 gene that is alternately spliced into four variants. The hematopoietic effects of SP and NK-A are mostly mediated via BM stroma. Array analyses with 2400 genes indicated distinct changes in SP-stimulated BM stroma. Computational analyses indicated networks of genes with hematopoietic regulation. Included among these networks is the high-mobility group box 1 gene (HMGB1), a nonhistone chromatin-associated protein. Validation studies indicated that NK-A could reverse SP-mediated HMGB1 decrease. Long-term culture-initiating cell assay, with or without NK-A receptor antagonist (NK2), showed a suppressive effect of HMGB1 on hematopoietic progenitors and increase in long-term culture-initiating cell assay cells (primitive hematopoietic cells). These effects occurred partly through NK-A. NSG mice with human hematopoietic system injected with the HMGB1 antagonist glycyrrhizin verified the in vitro effects of HMGB1. Although the effects on myeloid lineage were suppressed, the results suggested a more complex effect on the lymphoid lineage. Clonogenic assay for CFU– granulocyte-monocyte suggested that HMGB1 may be required to prevent hematopoietic stem cell exhaustion to ensure immune homeostasis. In summary, this study showed how HMGB1 is linked to SP and NK-A to protect the most primitive hematopoietic cell and also to maintain immune/hematopoietic homeostasis.

A 3D Bioprinted Material That Recapitulates the Perivascular Bone Marrow Structure for Sustained Hematopoietic and Cancer Models

“…Functional studies may require long-term cultures, e.g., studies to assess hematopoietic stem cells require > 6 wk cultures [ 76 ]. Therefore, to gauge the utility of 4:2 and 6:2 scaffolds for models associated with bone marrow functions, it was important to conduct analyses evaluating the stability of these scaffolds for long-term cultures.…”

High mobility group box 1 (HMGB1): a pivotal regulator of hematopoietic malignancies

“…Mechanistically, HMGB1 negatively regulates hematopoietic stimulation, while SP, a hematopoietic stimulator, decreases HMGB1 expression. Furthermore, NK-A can negatively regulate SP-mediated hematopoietic stimulation [ 77 – 79 ]. The dysfunction of HMGB1 may promote the occurrence and development of hematological malignancies by interfering with the hematopoietic function of the BM.…”

Restoration of aged hematopoietic cells by their young counterparts through instructive microvesicles release

“…These mice lack the major immune cells such as T-cells, B-cells, macrophages and NK cells. After 1 wk acclimatization, the NSG were humanized as described [ 67 – 69 ]. NSG mice were subjected to 150 cGy whole body γ-irradiation using a Mark-I cesium irradiator unit.…”