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Background  Adult human mesenchymal stem/stromal cells (hMSCs) from bone marrow have been reported to exhibit beneficial effects on spinal cord injury (SCI). A neuropeptide, pituitary adenylate cyclase-activating polypeptide (PACAP) is known to decrease neuronal cell death and inflammatory response after ischemia, SCI, and other neuronal disorders. Recently, we found that expression of the gene for mouse PACAP ( Adcyap1 ) was greater in animals receiving hMSCs with neural injury such as ischemia. However, the association of PACAP with hMSCs to protect nerve cells against neural injuries is still unclear.    Methods  Wild-type and PACAP-gene-deficient ( Adcyap1   +/−  ) mice were subjected to spinal cord transection, and hMSCs (5 × 10 5  cells) were injected into the intervertebral spinal cord on day 1 post-operation (p.o.). Locomotor activity, injury volume, retention of hMSCs, mouse and human cytokine genes (which contribute to macrophage (MΦ) and microglial activation), and  Adcyap1  were evaluated.    Results  hMSCs injected into wild-type mice improved locomotor activity and injury volume compared with vehicle-treated mice. In contrast, non-viable hMSCs injected into wild-type mice, and viable hMSCs injected into  Adcyap1   +/−   mice, did not. Wild-type mice injected with hMSCs exhibited increased  Adcyap1  expression, and observed PACAP immunoreaction in neuron-like cells. Gene expression levels for IL-1, tumor necrosis factor α (TNFα), interleukin-10 (IL-10), and transforming growth factor β (TGFβ) decreased, while that for interleukin-4 (IL-4) increased, in hMSC-injected wild-type mice. In contrast, IL-1, TGFβ, and IL-4 gene expression levels were all abolished in hMSC-injected  Adcyap1   +/−   mice on day 7 post-operation. Moreover, the mice-implanted hMSCs increased an alternative activating macrophage/microglial marker, arginase activity. The human gene profile indicated that hMSCs upregulated the gene of IL-4 and growth factors which were reported to enhance  Adcyap1  expression. Finally, we demonstrated that hMSCs express human  ADCYAP1  and its receptor gene after the inflammation-related interferon-γ (IFNγ)  in vitro .    Conclusions  These results suggest that hMSCs attenuate the deleterious effects of SCI by reducing associated inflammatory responses and enhancing IL-4 production. This effect could be mediated in part by cell-cell cross-talk involving the neuropeptide PACAP.    Electronic supplementary material  The online version of this article (doi:10.1186/s12974-015-0252-5) contains supplementary material, which is available to authorized users.

journal of neuroinflammation

Human mesenchymal stem/stromal cells suppress spinal inflammation in mice with contribution of pituitary adenylate cyclase-activating polypeptide (PACAP)