Abstract
Cell-based therapeutic strategies afford major potential advantages in the repair of injured tendons. Generation of induced pluripotent stem cells (iPSCs) expands cell sources for “regenerative” therapy. However, its application in tendon repair is still limited and the effects remain unclear. In this study, equine tenocyte-derived iPSCs (teno-iPSCs) were generated by expressing four Yamanaka factors. Compared to parental tenocytes and bone marrow derived mesenchymal stem cells (BMSCs), the transcriptional activities of lineage-specific genes, including Mkx, Col1A2, Col14, DCN, ELN, FMOD, and TNC, were highly repressed in the resulting teno-iPSCs. Exposure to cyclic uniaxial mechanical loading increased the expression of Scx, Egr1, Col1A2, DCN, and TNC in teno-iPSCs and the expression of Scx, Egr1, DCN, and TNC in BMSCs. Reintroduction of tenogenic transcription factor Mohawk (Mkx) upregulated the expression of DCN in teno-iPSCs and the expression of Scx, Col14, and FMOD in BMSCs. Mechanical loading combined with ectopic expression of equine Mkx further enhanced the expression of Egr1, Col1A2, DCN, and TNC in teno-iPSCs and the expression of Scx, Egr1, and TNC in BMSCs. These data suggest that the repressed lineage-specific genes in the teno-iPSCs can be re-activated by mechanical loading and ectopic expression of Mkx. Our findings offer new insights into the application of iPSCs for basic and clinic research in tendon repair.
Highlights
Tendon is a unique form of connective tissue that transmits the force from muscle to bone, allowing joint movement efficiently (Nourissat et al, 2015)
While Xu et al reported that human induced pluripotent stem cells (iPSCs)-derived neural crest stem cells could promote tendon repair in a rat patellar tendon window defect model(Xu et al, 2013), the study from Bavin et al showed that, compared to embryonic stem cells, equine fetal fibroblast-derived iPSCs had a reduced tendon differentiation capacity (Bavin et al, 2015)
Immunofluorescent staining with antibodies against Oct4, Sox2, Nanog, and TRA-1–81 confirmed the expression of pluripotency markers in the resulting iPSCs (Fig. 1E & S1)
Summary
Tendon is a unique form of connective tissue that transmits the force from muscle to bone, allowing joint movement efficiently (Nourissat et al, 2015). Cell-based tissue engineering approaches show great promise in tendon therapy, and a large number of cell populations, including tenocytes, mesenchymal stem cells (MSCs), embryonic stem cells (ESCs) and tendon progenitor/stem cells (TPSCs), have been proposed for tendon repair and regeneration under various conditions (Gaspar et al, 2015). IPSCs derived from differentiated somatic cells expand the cell sources and hold high potential for cell therapy and tissue engineering. Their application in tendon regeneration is still very limited and the effects remain debatable (Sun et al, 2015; Zhang et al, 2015; Czaplewski et al, 2014; Xu et al, 2013; Bavin et al, 2015). While Xu et al reported that human iPSC-derived neural crest stem cells could promote tendon repair in a rat patellar tendon window defect model(Xu et al, 2013), the study from Bavin et al showed that, compared to embryonic stem cells, equine fetal fibroblast-derived iPSCs had a reduced tendon differentiation capacity (Bavin et al, 2015)
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