2 13 Abstract 14 We have recently identified a population of cells within the peripheral nerves of adult mice that 15 can respond to BMP-2 exposure or physical injury to rapidly proliferate. More importantly, these 16 cells exhibited embryonic differentiation potentials that could be induced into osteoblastic and 17 endothelial cells in vitro. The current study examined human nerve specimens to compare and 18 characterize the cells after BMP-2 stimulation. Fresh pieces of human nerve tissue were minced 19 and treated with either BMP-2 (750ng/ml) or vehicle for 12 hours at 37°C, before digested in 20 0.2% collagenase and 0.05% trypsin-EDTA. Isolated cells were cultured in restrictive stem cell 21 medium. Significantly more cells were obtained from the nerve pieces with BMP-2 treatment in 22 comparison with the non-treated controls. Cell colonies were starting to form at day 3.23 Expressions of the 4 transcription factors Klf4, c-Myc, Sox2 and Oct4 were confirmed at both 24 transcriptional and translational levels. The cells can be maintained in the stem cell culture 25 medium for at least 6 weeks without changing morphologies. When the cells were switched to 26 fibroblast growth medium, dispersed spindle-shaped cells were noted and became fibroblast 27 activated protein-α (FAP) positive following immunocytochemistry staining. The data suggested 28 that human peripheral nerve tissue also contain a population of cells that can respond to BMP-2 29 and express all four transcription factors KLF4, Sox2, cMyc, and Oct4. These cells are capable to 30 differentiate into FAP-positive fibroblasts. It is proposed that these cells are possibly at the core 31 of a previously unknown natural mechanism for healing injury. 32 33 3 34 35 Introduction 36 The potential for stem cells to treat human disease is rightly perceived to be vast. Embryonic 37 stem cells (ESCs) from inner cell mass of mammalian blastocyst that have unlimited self-renewal 38 and pluripotency are capable of differentiate into ectodermal, mesodermal, and endodermal 39 cells [1, 2]. Based on the stud of previous, the ESCs behave undifferentiated morphology [3]. 40 Although there are numerous ongoing studies to investigate the therapeutic potentials of human 41 embryonic stem cells (hESCs) for type I diabetes (T1D), heart failure, Parkinson's disease and 42 inherited or acquired retinal degenerations [4], challenges remain to be conquered in clinical 43 development of hESCs such as legal and ethical issues, immune rejections, and differentiation 44 difficulties [3]. Somatic cells can be introduced to transform into a state of pluripotency [3]. The 45 brilliant work of Drs. Yamanaka and Takayashi [5, 6] demonstrated that pluripotent cells can be 46 created from adult differentiated cells by the virally induced manipulation of nuclear genes to 47 force expression of 4 specific transcription factors, octamer-binding transcription factor 4 (OCT4),48 sex determining region Y-box 2 (SOX2), Krüppel-like family of transcription factor 4 (KLF4) and c-49 Myc that will...