Regional Differences in Stem Cell/Progenitor Cell Populations from the Mouse Achilles Tendon

Abstract

Specific niches may affect how cells from different regions contribute to tendon biology, particularly in regard to the healing of certain tendinopathies. The objectives of this study are to determine whether distinct subpopulations of stem/progenitor cells are found within the tendon proper and the epi- and paratenon, the peritenon, as well as to characterize these stem/progenitor cell populations. In this study, we hypothesized that tendon stem/progenitor cells exist in each region, that these populations possess distinct features, and that these populations while multipotent could have differing potentials. To test this hypothesis, stem/progenitor cells were isolated and characterized from the peritenon and tendon proper of mouse Achilles tendons. Colony-forming unit and multipotency assays, as well as flow cytometry, and real-time quantitative polymerase chain reaction analyses of stem cell markers were performed. Significantly, more stem/progenitor cell colonies were observed from cells derived from the tendon proper relative to the peritenon. Analysis of surface markers for stem/progenitor cells from both regions indicated that they were Sca1(+) (stem cell marker), Cd90(+) and Cd44(+) (fibroblast markers), Cd18(-) (leukocyte marker), Cd34(-) (hematopoietic and vascular marker), and Cd133(-) (perivascular marker). Tendon proper stem/progenitor cells had increased expression levels for tenomodulin (Tnmd) and scleraxis (Scx), indicative of enrichment of stem/progenitor cells of a tendon origin. In contrast, cells of the peritenon demonstrated relative increases in the vascular (endomucin) and pericyte (Cd133) markers relative to cells from the tendon proper. Stem/progenitor cells from both regions were multipotent (adipogenic, chondrogenic, osteogenic, and tenogenic). These findings demonstrated that different progenitor populations exist within discrete niches of the Achilles tendon-tendon proper versus peritenon. Overall, these data support the hypothesis that the progenitor pools from both regions have distinct properties and contain enriched progenitor subpopulations of different origins. Moreover, in considering their roles in tendon healing more broadly, they are potential cell sources that may differentially contribute to intrinsic and extrinsic tendon repair mechanisms. That is, intrinsic repair may require a progenitor class with predominant tendon marker expression, while extrinsic repair may involve a progenitor class recruited from perivascular cells of the peritenon.

In Vivo Identity of Tendon Stem Cells and the Roles of Stem Cells in Tendon Healing

“…While all the LRCs were seen embedded between parallel collagen fibers at the tendon mid-substance, some LRCs were found at the perivascular niche at the peritenon. Mienaltowski et al [23] also reported the existence of different stem/progenitor cell populations within distinct niches at the tendon mid-substance and peritenon; and the stem/progenitor cells at the peritenon might be more vascular in origin. Bi et al [3] reported the residence and alignment of LRCs in-between long parallel collagen fibrils containing biglycan and fibromodulin [3].…”

“…Bi et al [3] reported the residence and alignment of LRCs in-between long parallel collagen fibrils containing biglycan and fibromodulin [3]. The significance of localization of IdU + cells at the peritenon and the mid-substance was not clear but might be important for extrinsic and intrinsic repair of tendon, respectively [23].…”

Restricted differentiation potential of progenitor cell populations obtained from the equine superficial digital flexor tendon (SDFT)

“…TSPCs possess similar properties to mesenchymal stem cells (MSCs) and have been identified by the expression of cell surface and stem‐cell markers, and a capacity for self‐renewal and multi‐lineage differentiation. TSPCs are thought to be tenocyte precursors and can be induced to differentiate into osteocytes, chondrocytes, and adipocytes in vitro and in vivo 8, 9, 10, 11, 12…”

A MINI REVIEW ON THE BASIC KNOWLEDGE ON TENDON: REVISITING THE NORMAL & INJURED TENDON

“…The former postulates that fibroblast populations come from the endotenon and epitenon, whereas the latter postulates that inflammatory cells and fibroblasts migrate in from surrounding tissues (56). However, a recent report suggested that intrinsic repair may require a progenitor class with predominant tendon marker expression, while extrinsic repair may involve a progenitor class recruited from perivascular cells of the peritenon (57). Tendon TSC/TPC decreases with age and alludes to its association with the age-related reduction in tendon repair as seen in rotator cuff tears (58).…”