The Behavior of Tendon Progenitor Cells from Tendinopathic Tendons: Implications for Treatment

Abstract

Tendinopathy remains a significant clinical challenge. Although there is some evidence that leukocyte-rich platelet-rich plasma can improve the symptoms of tendinopathy, more efficacious treatments will be required in the future to improve probability of successfully resolving this condition in athletes. Because optimal treatments are not currently available, there is a need to better understand the pathology of tendinopathy from the perspective of tendon progenitor cells (TPCs). TPCs isolated from normal and tendinopathy donors were characterized by their stem cell properties and proliferation capacities, along with their ability to become tenocytes under mechanical loading. The results showed a significant 2.6-fold increase in the viable cell population in tendinopathy versus normal donors. Although the percentage of self-renewing cells was similar, the total number of TPCs in tendinopathy was significantly higher (1.6-fold) than normal TPCs based on the colony formation assays. In contrast, TPCs from tendinopathy tissue showed significantly lower cellular proliferation rate by cumulative population doublings. Next, the expanded TPCs from both tissues successfully demonstrated the trilineage differentiation capabilities with specific gene markers, staining, and biochemical assays. To induce tenogenic differentiation, stretchable silicone wells were designed and fabricated, plus the creation of an adaptor platform used on a syringe pump for mechanical stretch. This economic design provided the adequate cyclic loading to drive tenogenic differentiation. With these devices, the stretch duration was optimized and showed the significant increase in scleraxis (SCX) and tenomodulin (TNMD) expression at 2.60 (fold change) and 3.86 (fold change in logarithm), respectively, by reverse transcription-quantitative polymerase chain reaction in normal TPCs after stretch. This assay also demonstrated the widespread cell reorientation following stretch in normal TPCs. In contrast, the mechanical loading did not increase the SCX gene expression; TNMD expression remained undetectable, and cell realignment was significantly less in tendinopathy TPCs. In addition, western blot analysis confirmed the elevated TNMD protein expression in normal TPCs following stretch and the lack of expression in tendinopathy TPCs. In summary, tendinopathy TPCs were unable to differentiate into tenocytes following mechanical stretch. Future studies may aim to reprogram tendinopathy TPCs to allow tenogenic induction.

Tendon-Derived Progenitor Cells With Multilineage Potential Are Present Within Human Patellar Tendon

“… 58 Additionally, another study has reported that despite a higher number of total resident TDPCs in tendinopathic tissue, these TDPCs are unable to differentiate into tenocytes to regulate the extracellular matrix (ECM). 5 …”

“…58 Additionally, another study has reported that despite a higher number of total resident TDPCs in tendinopathic tissue, these TDPCs are unable to differentiate into tenocytes to regulate the extracellular matrix (ECM). 5 The difficulty in treating tendinopathy lies in the multifactorial pathogenesis of the disease. The utilization of tendon derived stem cells (TDSC) as a biologic agent may address many of these aberrant pathways.…”

Rat Plantar Fascia Stem/Progenitor Cells Showed Lower Expression of Ligament Markers and Higher Pro-Inflammatory Cytokines after Intensive Mechanical Loading or Interleukin-1β Treatment In Vitro

“…Among different non-exclusive pathogenic mechanisms of tendinopathy, altered fate of stem cells after tendon injury has been suggested as an important pathogenic mechanism [ 16 , 17 ]. The functions of tendon-derived stem/progenitor cells (TDSCs) isolated from tendinopathy patients were altered [ 18 , 19 , 20 ]. More TDSCs, with a lower proliferative capacity and tenogenic potential, but with a higher cellular senescence, non-tenocyte differentiation potential, and inflammatory response, were present in an inflammatory collagenase-induced degenerative failed tendon healing animal model [ 21 , 22 ] and clinical samples of tendinopathy [ 18 , 19 , 20 ].…”

“…The functions of tendon-derived stem/progenitor cells (TDSCs) isolated from tendinopathy patients were altered [ 18 , 19 , 20 ]. More TDSCs, with a lower proliferative capacity and tenogenic potential, but with a higher cellular senescence, non-tenocyte differentiation potential, and inflammatory response, were present in an inflammatory collagenase-induced degenerative failed tendon healing animal model [ 21 , 22 ] and clinical samples of tendinopathy [ 18 , 19 , 20 ]. Tendinopathic TDSCs were unable to differentiate into tenocytes following mechanical stretch [ 18 ].…”

“…More TDSCs, with a lower proliferative capacity and tenogenic potential, but with a higher cellular senescence, non-tenocyte differentiation potential, and inflammatory response, were present in an inflammatory collagenase-induced degenerative failed tendon healing animal model [ 21 , 22 ] and clinical samples of tendinopathy [ 18 , 19 , 20 ]. Tendinopathic TDSCs were unable to differentiate into tenocytes following mechanical stretch [ 18 ]. We hypothesized that the fate of the resident plantar fascia stem/progenitor cells would be altered after mechanical overuse similar to tendinopathy and contribute to the pathogenesis of plantar fasciitis.…”