Stem cells represent a unique population of cells with self-renewal capacity. However, the molecular control of self-renewal and differentiationof stem cells has remained enigmatic. Here, we show that short-type PB-cadherin (STPB-C) promoted self-renewal of spermatogonial stem cells(SSCs) via activating Janus kinase/signal transducer and activator of transcription (JAK-STAT) and phosphoinositide-3 kinase (PI3-K)/Akt, andblocking transforming growth factor (TGF)-β1 signaling. These data were obtained with varied approaches, including the use of RNA interference(RNAi), SSC cultures infected by STPB-C retroviral vector, bromodeoxyuridine (BrdU) incorporation assay, and other techniques. These findingshave important implications for germ cell biology and create the possibility of using SSCs for biotechnology and medicine. They are also criticalin understanding tissue homeostasis, the aging process, tumor formation and degenerative diseases.