Are Bone Marrow Mesenchymal Stem Cells-Induced Tenogenic Progenitor Cells Identical to Tendon Progenitor Cells?

I n a recent article published in this journal by Alberton and colleagues, a stable ectopic expression of Scx in human bone marrow mesenchymal stem cells (BM-hMSC) was established and these generated hMSC-Scx cells exhibited a tenogenic phenotype with reduced cell proliferation, and multipotentiality [1]. This clonal hMSC-Scx cell line was termed as a homogeneous population of committed tendon progenitor cells [1]. Although the standard induction and evaluation protocols for the tenogenic differentiation of stem cells have not been well established, more and more recent studies focused on tenogenic differentiation of different stem cells for tendon regeneration [2]. The results from this study added more useful information about how to regulate BM-hMSC to tenogenic progenitor states by using stable lentiviral Scx transduction. Actually, BM-hMSCs in this study were induced into committed tenogenic progenitor cells, not into tendon progenitor cells, after being transduced with FLAG-Scx cDNA lentivirally in vitro. The usage of tendon progenitor cells in the article may lead to misunderstanding in the readers. Are these bone marrow mesenchymal stem cells (BMSCs)-induced tenogenic progenitor cells identical to tendon progenitor cells? To our knowledge, tendon progenitor cells are early descendants of tendon stem cells. They and their ancestor, tendon stem cells, represent a unique cell population resident in tendon tissues, which are distinct from tenocytes. Recently, several lines of evidence suggested that multipotent stem/progenitor cells also existed in human and animal tendon tissues, in addition to bone marrow [3 –7]. These tendon stem/progenitor cells (TSPCs) are mixture of tendon stem cells and tendon progenitor cells. The characteristics of TSPCs were identified in vitro and in vivo by comparing with BMSCs, including their cell morphology, phenotypes, proliferation, and differentiation characteristics. Briefly, murine and rat TSPCs were reported to be morphologically different from that of BMSCs [3,4] while human TSPCs were relatively homogeneous and similar to BM-hMSCs [3]. Phenotypically, TSPCs expressed CD44, CD73, CD90, CD90.1, CD90.2, CD105, Stro-1, Sca-1, CD146, nucelostemin, Oct-4, and SSEA-4 but were negative for CD31, CD34, CD18, CD117, CD45, Flk-1, CD144, and CD106 [3 –8]. While TSPCs expressed many of the same stem/progenitor cell markers as BMSCs, they also expressed some unique phenotypes. Specifically, all mouse TSPCs expressed type I collagen, whereas only a certain population of mouse BMSCs expressed this protein [3]. On the other hand, expression of alpha-smooth muscle actin was more abundant in mouse BMSCs than in mouse TSPCs [3]. More human and mouse TSPCs than BMSCs expressed cartilage oligomeric protein (Comp) and tenascin C. All human TSPCs and BMSCs expressed fibronectin, but none expressed type II collagen [3]. Rat TSPCs exhibited higher proliferative potential and expressed higher level of tenogenic, osteogenic, adipogenic, and chondrogenic markers/activity both at basal level and upon induction [9]. Human and mouse TSPCs and BMSCs could also respond to some growth factors, such as bone morphogenic protein-2 (BMP-2) and transforming growth factor beta-1 [3]. Rat TSPCs showed higher expression of BMP receptors (IA, IB and II) and BMP-2-induced osteogenesis when compared with BMSCs [10]. All these data suggested that TSPCs represent a unique stem/progenitor cell population in tendon tissues, which are distinct from BMSCs. The roles of TSPCs in tendon pathology [11 –13] and their potential for tendon/tendon bone junction tissue engineering applications [6,14 –16] are attracting more and more interest in clinicians and researchers. Although current evidence on the unique properties of TSPCs is still limited and the exact characteristics of tendon progenitor cells were also not fully investigated, which are due to the lack of specific markers to identify tendon progenitor cells from tendon stem cells, it should be aware that TSPCs, as tendon tissue specific stem/progenitor cells, represent a unique cell population in tendon, and tendon progenitor cells are the early descendants of tendon stem cells. The unique properties of TSPCs mentioned above can partly reflect some characteristics of tendon progenitor cells as these TSPCs also include tendon progenitor cells. Based on the findings in this article, we agree that BM-hMSCs were induced and committed to tenogenic progenitor cells by transducing with FLAG-Scx cDNA lentivirally. However, the true state and function of these tenogenic differentiated progenitor cells remains largely undefined. The difference between these BM-hMSCs-induced tenogenic progenitor cells and tendon progenitor cells are still unknown. Further in vitro and in vivo characterization of these BM-hMSCs-induced tenogenic progenitor cells, compared with tendon progenitor cells, is necessary before usage of this novel hMSC-Scx cell line in tendon/ligament research.