Pituitary adenylate cyclase-activating polypeptide (PACAP) contributes to the proliferation of hematopoietic progenitor cells in murine bone marrow via PACAP-specific receptor

Sci Rep. 2016 Feb 29;6:22373. doi: 10.1038/srep22373.


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.

MeSH terms

  • Animals
  • Antigens, CD34 / metabolism
  • Bone Marrow / metabolism
  • Cell Proliferation
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • Granulocytes / cytology
  • Hematopoiesis / genetics*
  • Hematopoietic Stem Cells / metabolism*
  • Ki-67 Antigen / genetics
  • Ki-67 Antigen / metabolism
  • Macrophages / cytology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pituitary Adenylate Cyclase-Activating Polypeptide / genetics
  • Pituitary Adenylate Cyclase-Activating Polypeptide / metabolism*
  • RNA, Messenger / genetics
  • Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / genetics
  • Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / metabolism*
  • Sympathetic Nervous System / metabolism*


  • Adcyap1 protein, mouse
  • Adcyap1r1 protein, mouse
  • Antigens, CD34
  • Ccnd1 protein, mouse
  • Ki-67 Antigen
  • Pituitary Adenylate Cyclase-Activating Polypeptide
  • RNA, Messenger
  • Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
  • Cyclin D1