Neurotrophically Induced Mesenchymal Progenitor Cells Derived from Induced Pluripotent Stem Cells Enhance Neuritogenesis via Neurotrophin and Cytokine Production

• Published in: Stem cells translational medicine 2018-01, Vol.7 (1), p.45-58
• Main Authors: Brick, Rachel M., Sun, Aaron X., Tuan, Rocky S.
• Format: Article
• Language: English
• Subjects: Axonogenesis; Bone marrow; Brain-derived neurotrophic factor; Cell culture; Cytokines; Dorsal root ganglia; Fibroblasts; Gene expression; Growth factors; Health aspects; Immunoglobulins; Induced Pluripotent stem cells; Leukemia inhibitory factor; Life span; Mesenchymal Stem Cells; Mesenchyme; Nanofiber scaffold; Nerve growth; Nerve repair; Neuropathy; Neuroprotection; Neurotrophins; Osteonectin; Osteopontin; Penicillin; Peripheral nerves; Pluripotency; Pluripotent Stem Cells; Progenitor cells; Regeneration; Regenerative medicine; Schwann cells; Secretome; Sholl analysis; Signal transduction; Stat3 protein; Stem cells; Tissue engineering; Translational s and Reviews; Transplants & implants
• ISSN: 2157-6564; 2157-6580; 2157-6580
• DOI: 10.1002/sctm.17-0108

Adult tissue‐derived mesenchymal stem cells (MSCs) are known to produce a number of bioactive factors, including neurotrophic growth factors, capable of supporting and improving nerve regeneration. However, with a finite culture expansion capacity, MSCs are inherently limited in their lifespan and use. We examined here the potential utility of an alternative, mesenchymal‐like cell source, derived from induced pluripotent stem cells, termed induced mesenchymal progenitor cells (MiMPCs). We found that several genes were upregulated and proteins were produced in MiMPCs that matched those previously reported for MSCs. Like MSCs, the MiMPCs secreted various neurotrophic and neuroprotective factors, including brain‐derived neurotrophic factor (BDNF), interleukin‐6 (IL‐6), leukemia inhibitory factor (LIF), osteopontin, and osteonectin, and promoted neurite outgrowth in chick embryonic dorsal root ganglia (DRG) cultures compared with control cultures. Cotreatment with a pharmacological Trk‐receptor inhibitor did not result in significant decrease in MiMPC‐induced neurite outgrowth, which was however inhibited upon Jak/STAT3 blockade. These findings suggest that the MiMPC induction of DRG neurite outgrowth is unlikely to be solely dependent on BDNF, but instead Jak/STAT3 activation by IL‐6 and/or LIF is likely to be critical neurotrophic signaling pathways of the MiMPC secretome. Taken together, these findings suggest MiMPCs as a renewable, candidate source of therapeutic cells and a potential alternative to MSCs for peripheral nerve repair, in view of their ability to promote nerve growth by producing many of the same growth factors and cytokines as Schwann cells and signaling through critical neurotrophic pathways. Stem Cells Translational Medicine 2018;7:45–58 Mesenchymal progenitors cells derived from induced pluripotent stem cells produce factors that act on explant cultures of embryonic cultures of embryonic dorsal root ganglion to enhance neurite outgrowth and complexity, as well as axon elongation on aligned, electrospun nanofibrous substrate.