Adipose Tissue‐Derived Stem Cells Secrete CXCL5 Cytokine with Neurotrophic Effects on Cavernous Nerve Regeneration

Previously we reported that paracrine actions likely mediated the therapeutic effects of adipose tissue‐derived stem cells (ADSCs) on a rat model of cavernous nerve (CN) injury. To identify potential neurotrophic factors in ADSC's secretion, test the most promising one, and identify the molecular mechanism of its neurotrophic action. Rat major pelvic ganglia (MPG) were cultured in conditioned media of ADSC and penile smooth muscle cells (PSMCs). Cytokine expression in these two media was probed with a cytokine antibody array. CXCL5 cytokine was quantified in these two media by enzyme‐linked immunosorbent assay (ELISA). Activation of Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) by CXCL5 was tested in neuroblastoma cell lines BE(2)C and SH‐SY5Y as well as in Schwann cell line RT4‐D6P2T by Western blot. Involvement of CXCL5 and JAK/STAT in ADSC‐conditioned medium's neurotrophic effects was confirmed with anti‐CXCL5 antibody and JAK inhibitor AG490, respectively. Neurotrophic effects of ADSC and PSMC‐conditioned media were quantified by measuring neurite length in MPG cultures. Secretion of CXCL5 in these two media was quantified by ELISA. Activation of JAK/STAT by CXCL5 was quantified by densitometry on Western blots for STAT1 and STAT3 phosphorylation. MPG neurite length was significantly longer in ADSC than in PSMC‐conditioned medium. CXCL5 was secreted eight times higher in ADSC than in PSMC‐conditioned medium. Anti‐CXCL5 antibody blocked the neurotrophic effects of ADSC‐conditioned medium. CXCL5 activated JAK/STAT concentration‐dependently from 0 to 50 ng/mL in RT4‐D6P2T Schwann cells. At 50 ng/mL, CXCL5 activated JAK/STAT time‐dependently, peaking at 45 minutes. AG490 blocked these activities as well as the neurotrophic effects of ADSC‐conditioned medium. CXCL5 was secreted by ADSC at a high level, promoted MPG neurite growth, and activated JAK/STAT in Schwann cells. CXCL5 may contribute to ADSC's therapeutic efficacy on CN injury‐induced ED. Zhang H, Yang R, Wang Z, Lin G, Lue TF, and Lin C‐S. Adipose tissue‐derived stem cells secrete CXCL5 cytokine with neurotrophic effects on cavernous nerve regeneration. J Sex Med 2011;8:437–446.