Concise Review: Stem Cell Fate Guided By Bioactive Molecules for Tendon Regeneration

Abstract

Tendon disorders, which are commonly presented in the clinical setting, disrupt the patients’ normal work and life routines, and they damage the careers of athletes. However, there is still no effective treatment for tendon disorders. In the field of tissue engineering, the potential of the therapeutic application of exogenous stem cells to treat tendon pathology has been demonstrated to be promising. With the development of stem cell biology and chemical biology, strategies that use inductive tenogenic factors to program stem cell fate in situ are the most easily and readily translatable to clinical applications. In this review, we focus on bioactive molecules that can potentially induce tenogenesis in adult stem cells, and we summarize the various differentiation factors found in comparative studies. Moreover, we discuss the molecular regulatory mechanisms of tenogenesis, and we examine the various challenges in developing standardized protocols for achieving efficient and reproducible tenogenesis. Finally, we discuss and predict future directions for tendon regeneration. Stem Cells Translational Medicine 2018;7:404–414

In Vitro Innovation of Tendon Tissue Engineering Strategies

“…This evidence seems to suggest that a physiological tendon-inductive microenvironment requires multiple GFs over a specific temporal pattern and an optimized relative ratio [3,379]. This complexity is likely the explanation for the lack to date of reproducible GFs formulations for the induction of in vitro tenogenesis despite the consensus positions available for osteogenesis and chondrogenesis [51,384]. However, several efforts have been made to validate the in vitro delivery of GFs for tenogenesis, as demonstrated by the scientometric analysis ( Figure 10).…”

“…The transforming growth factor beta (TGF-β) pathway is the most recognized signaling pathway for tendon development [380]. It is active in all stages of tendon healing, and its expression is upregulated in differentiated tendon cells [115,382,384,385]. TGF-β induces extrinsic cell migration, regulates proteinases and cell proliferation, and stimulates collagen production.…”

Mechanical and molecular parameters that influence the tendon differentiation potential of C3H10T1/2 cells in 2D- and 3D-culture systems

“…Based on specific lineage markers and identified master genes, established protocols are now recognized to drive differentiation towards osteocytes, chondrocytes and adipocytes (Caplan, 1991;Pittenger et al, 1999;Prockop, 1997). Although studies identify tendon cell differentiation upon molecular and mechanical cues from MSCs (reviewed in Nourissat et al, 2015;Zhang et al, 2018), tendon lineage is less studied than other tissue-specific lineages. There is no recognized/established protocol with external inducers to differentiate MSCs towards a tendon phenotype.…”

Mechanisms of Action of Multipotent Mesenchymal Stromal Cells in Tendon Disease

“…An extensive body of recent literature describes the tenogenic differentiation of MSC in response to a wide range of stimuli, although unfortunately, no generally accepted in vitro model or standard tenogenic differentiation assay exists. Current concepts of tenogenic differentiation are reviewed in detail elsewhere [146,147]. The most commonly used stimuli to induce tenogenesis in MSC include growth factors, scaffolds with specific topography, and cyclic mechanical loading, with most studies combining two or more of these approaches, based on earlier studies in the field of tissue engineering [37,[148][149][150].…”