Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP, encoded by adcyap1) plays an important role in ectodermal development. However, the involvement of PACAP in the development of other germ layers is still unclear. This study assessed the expression of a PACAP-specific receptor (PAC1) gene and protein in mouse bone marrow (BM). Cells strongly expressing PAC1+ were large in size, had oval nuclei, and merged with CD34+ cells, suggesting that the former were hematopoietic progenitor cells (HPCs). Compared with wild-type mice, adcyap1−/− mice exhibited lower multiple potential progenitor cell populations and cell frequency in the S-phase of the cell cycle. Exogenous PACAP38 significantly increased the numbers of colony forming unit-granulocyte/macrophage progenitor cells (CFU-GM) with two peaks in semi-solid culture. PACAP also increased the expression of cyclinD1 and Ki67 mRNAs. These increases were completely and partially inhibited by the PACAP receptor antagonists, PACAP6-38 and VIP6-28, respectively. Little or no adcyap1 was expressed in BM and the number of CFU-GM colonies was similar in adcyap1−/− and wild-type mice. However, PACAP mRNA and protein were expressed in paravertebral sympathetic ganglia, which innervate tibial BM, and in the sympathetic fibers of BM cavity. These results suggested that sympathetic nerve innervation may be responsible for PACAP-regulated hematopoiesis in BM, mainly via PAC1.
Highlights
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a multifunctional neuropeptide belonging to the glucagon-secretin-vasoactive intestinal peptide (VIP) family
We recently found that adcyap[1] and adcyap1r1 were expressed in cultured human bone marrow mesenchymal stromal cells stimulated with interferon-γ, but not in untreated cells[26]
The initial step in investigating the association between PACAP and hematopoietic cells was to determine the expression of genes encoding the three PACAP receptors, vipr[1], vipr[2] and adcyap1r1, in nucleated bone marrow (BM) cells and blood (Fig. 1a)
Summary
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a multifunctional neuropeptide belonging to the glucagon-secretin-vasoactive intestinal peptide (VIP) family. Mouse embryonic stem (ES) cells were found to be positive for adcyap1r1 and vipr[2], which encodes VPAC223, suggesting that PACAP may be involved in development of other germ cell layers. Strong PAC1 immunopositivity was observed in larger size cells with oval nuclei that merged with CD34+ cells, suggesting that the former were HPCs. BM in adcyap1−/− mice exhibited lower multiple potential progenitor cell populations and cell frequency in the S-phase of the cell cycle compared with BM in wild-type mice. PACAP increased the expression of cell-cycle related cyclin D1 (ccnd1) and Ki67 (mki67) genes. Taken together, these findings suggested that PACAP in BM may derive from innervating sympathetic fibers
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