title: The microenvironment-specific transformation of adult stem cells models malignant triton tumors.
abstract: Here, we demonstrated the differentiation potential of murine muscle-derived stem/progenitor cells (MDSPCs) toward myogenic, neuronal, and glial lineages. MDSPCs, following transplantation into a critical-sized sciatic nerve defect in mice, showed full regeneration with complete functional recovery of the injured peripheral nerve at 6 weeks post-implantation. However, several weeks after regeneration of the sciatic nerve, neoplastic growths were observed. The resulting tumors were malignant peripheral nerve sheath tumors (MPNSTs) with rhabdomyoblastic differentiation, expressing myogenic, neurogenic, and glial markers, common markers of human malignant triton tumors (MTTs). No signs of tumorigenesis were observed 17 weeks post-implantation of MDSPCs into the gastrocnemius muscles of dystrophic/mdx mice, or 1 year following subcutaneous or intravenous injection. While MDSPCs were not oncogenic in nature, the neoplasias were composed almost entirely of donor cells. Furthermore, cells isolated from the tumors were serially transplantable, generating tumors when reimplanted into mice. However, this transformation could be abrogated by differentiation of the cells toward the neurogenic lineage prior to implantation. These results establish that MDSPCs participated in the regeneration of the injured peripheral nerve but transformed in a microenvironment- and time-dependent manner, when they likely received concomitant neurogenic and myogenic differentiation signals. This microenvironment-specific transformation provides a useful mouse model for human MTTs and potentially some insight into the origins of this disease.
authors.affiliation: Stem Cell Research Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States of America ; Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America ; Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Mitra
authors.initials: M
authors.lastname: Lavasani
authors.affiliation: Stem Cell Research Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States of America ; Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America ; Allegheny-Singer Research Institute, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Pollett
authors.affiliation: Stem Cell Research Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States of America ; Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Arvydas
authors.initials: A
authors.lastname: Usas
authors.affiliation: Stem Cell Research Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States of America ; Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Seth D
authors.initials: SD
authors.lastname: Thompson
authors.affiliation: Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada ; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Aaron F
authors.initials: AF
authors.lastname: Pollett
authors.affiliation: Stem Cell Research Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States of America ; Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America ; Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America ; Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Johnny
authors.initials: J
authors.lastname: Huard
mesh_terms: D000328:Adult; D053687:Adult Stem Cells / Q000473:pathology*; D000818:Animals; D002454:Cell Differentiation; D019070:Cell Lineage; D002469:Cell Separation; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D060833:Cellular Microenvironment; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D024510:Muscle Development; D018482:Muscle, Skeletal / Q000473:pathology; D009416:Nerve Regeneration; D009442:Neurilemmoma / Q000473:pathology* / Q000503:physiopathology; D055495:Neurogenesis; D009457:Neuroglia / Q000166:cytology; D020127:Recovery of Function; D012583:Schwann Cells / Q000166:cytology; D012584:Sciatic Nerve / Q000473:pathology / Q000503:physiopathology; D055153:Stem Cell Niche; D033581:Stem Cell Transplantation