Platelet HMGB1 in Platelet-Rich Plasma Promotes Tendon Wound Healing

AbstractPlatelet-rich plasma (PRP) is a widely used autologous treatment for tendon injuries in clinics, but clinical trials often produce conflicting results. Platelets (PLTs) are a major source of high mobility group box1 (HMGB1) that is gaining attention as a chemoattractant that can recruit stem cells to the wound area to enhance healing; however, the contribution of PLT HMGB1 in wounded tendon healing remains unexplored. This study investigated the effect of PLT HMGB1 within PRP to enhance healing in an acute patellar tendon injury model in PLT HMGB1 knockout (KO) mice and GFP mice. A window defect was created in the patellar tendons of both groups of mice, and wounds were treated with either saline, PRP isolated from PLT HMGB1 KO mice, or PRP isolated from GFP mice. Seven days post-treatment, animals were sacrificed and analyzed by gross inspection, histology, and immunostaining for characteristic signs of tendon healing and repair. Our results showed that in comparison to mice treated with PRP from PLT HMGB1-KO mice, wounds treated with PRP from GFP mice healed faster and exhibited a better organization in tendon structure. Mice treated with PRP from PLT HMGB1-KO mice produced tendon tissue with large premature wound areas and low cell densities. However, wounds of PLT HMGB1 KO mice showed better healing with PRP from HMGB1 KO mice compared to saline treatment. Moreover, wounds treated with PRP from GFP mice had increased extracellular HMGB1, decreased CD68, increased stem cell markers CD146 and CD73, and increased collagen III protein expression levels compared to those treated with PRP from PLT HMGB1 KO mice. Thus, PLT HMGB1 within PRP plays an important role in the healing of wounded tendon. Our findings also suggest that the efficacy of PRP treatment for tendon injuries in clinics may be affected by PLT HMGB1 within PRP preparations.

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Platelet HMGB1 in Platelet-Rich Plasma (PRP) promotes tendon wound healing

PLoS ONE ◽

10.1371/journal.pone.0251166 ◽

2021 ◽

Vol 16 (9) ◽

pp. e0251166

Author(s):

Jianying Zhang ◽

Feng Li ◽

Tyler Augi ◽

Kelly M. Williamson ◽

Kentaro Onishi ◽

...

Keyword(s):

Stem Cells ◽

Wound Healing ◽

Platelet Rich Plasma ◽

Tendon Healing ◽

High Mobility ◽

Tendon Injuries ◽

Stem Cell Markers ◽

Wound Area ◽

Collagen Iii ◽

Cell Densities

Platelet-rich plasma (PRP) is a widely used autologous treatment for tendon injuries in clinics. Platelets (PLTs) are a major source of high mobility group box1 (HMGB1) that is gaining attention as a chemoattractant that can recruit stem cells to the wound area to enhance healing of injured tissues; however, the contribution of PLT HMGB1 in wounded tendon healing remains unexplored. This study investigated the effect of PLT HMGB1 within PRP on tendon healing using PLT HMGB1 knockout (KO) and GFP mice. A window defect was created in the patellar tendons of both groups of mice, and wounds were treated with either saline, PRP isolated from PLT HMGB1-KO mice, or PRP isolated from GFP mice. Seven days post-treatment, animals were sacrificed and analyzed by gross inspection, histology, and immunostaining for characteristic signs of tendon healing and repair. Our results showed that in comparison to mice treated with PRP from PLT HMGB1-KO mice, wounds treated with PRP from GFP mice healed faster and exhibited a better organization in tendon structure. Mice treated with PRP from PLT HMGB1-KO mice produced tendon tissue with large premature wound areas and low cell densities. However, wounds of PLT HMGB1-KO mice showed better healing with PRP from HMGB1-KO mice compared to saline treatment. Moreover, wounds treated with PRP from GFP mice had increased extracellular HMGB1, decreased CD68, increased stem cell markers CD146 and CD73, and increased collagen III protein expression levels compared to those treated with PRP from PLT HMGB1-KO mice. Thus, PLT HMGB1 within PRP plays an important role in tendon wound healing by decreasing inflammation, increasing local HMGB1 levels, and recruiting stem cells to the wound area in the tendon. Our findings also suggest that the efficacy of PRP treatment for tendon injuries in clinics may depend on PLT HMGB1 within PRP preparations.

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Selectively activated PRP exerts differential effects on tendon stem/progenitor cells and tendon healing

Journal of Tissue Engineering ◽

10.1177/2041731418820034 ◽

2019 ◽

Vol 10 ◽

pp. 204173141882003 ◽

Cited By ~ 4

Author(s):

Jianying Zhang ◽

Daibang Nie ◽

Kelly Williamson ◽

Jorge L Rocha ◽

MaCalus V Hogan ◽

...

Keyword(s):

Blood Vessels ◽

Progenitor Cells ◽

Platelet Rich Plasma ◽

Tendon Healing ◽

Tendon Injury ◽

Collagen I ◽

Chronic Type ◽

Wound Area ◽

Differential Effects ◽

Matrix Metalloproteinase 1

To understand the variable efficacy with platelet rich plasma (PRP) treatments for tendon injury, we determined the differential effects of proteinase-activated receptor (PAR)1- or PAR4-activated PRP (PAR1-PRP, PAR4-PRP) from humans on human patellar tendon stem/progenitor cells (TSCs) and tendon healing. We show that PAR1-PRP released VEGF, whereas PAR4-PRP released endostatin. Treatment of TSCs with PAR1-PRP increased collagen I expression and matrix metalloproteinase-1 (MMP-1), but cells treated with PAR4-PRP increased less collagen I and higher MMP-2 expression. The wound area treated with PAR4-PRP formed tendon-like tissues with well-organized collagen fibers and fewer blood vessels, while PAR1-PRP treatment resulted in the formation of blood vessels and unhealed tissues. These findings indicate that differential activation of PRP leads to different effects on TSCs and tendon healing. We suggest that based on acute or chronic type of tendon injury, selective activation of PRP should be applied in clinics in order to treat injured tendons successfully.

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Tendon Stem Cells and Platelet-Rich Plasma for Repair of Injured Tendons

ASME 2011 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2011-53204 ◽

2011 ◽

Author(s):

James H-C. Wang

Keyword(s):

Stem Cells ◽

Sports Medicine ◽

Platelet Rich Plasma ◽

Normal Structure ◽

Critical Issue ◽

Tendon Injury ◽

Tendon Injuries ◽

Differentiation Potential ◽

Tendon Stem Cells ◽

Differential Properties

Tendon injuries, including acute tendon injuries and tendinopathy, are common in both occupational and athletic settings. However, current treatments for tendon injury are largely ineffective, as they cannot restore normal structure and function to injured tendons. This challenge mainly stems from our incomplete understanding of tendon cell properties and responses to biomechanical and biochemical environments surrounding the cells. In recent years, however, significant progress has been made on two fronts. First, tendon stem cells (TSCs) have been recently identified. The tendon-specific stem cells can self-renew and posses multi-differentiation potential and as such, may be used to repair injured tendons more effectively. Second, platelet-rich plasma (PRP) has now been widely used in orthopaedics and sports medicine to treat injured tendons. In this presentation, I will present data on TSCs, in terms of their differential properties with respect to tenocytes and their differential mechano-responses when subjected to small and large mechanical loading conditions. I will also discuss the basic scientific studies on PRP regarding its effects on TSCs, particularly on their differentiation, which is a critical issue related to the safety and efficacy of PRP treatment in clinics (Fig. 1).

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Nonwoven-based gelatin/polycaprolactone membrane loaded with ERK inhibitor U0126 for treatment of tendon defects

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02679-x ◽

2022 ◽

Vol 13 (1) ◽

Author(s):

Yonghui Hou ◽

Bingyu Zhou ◽

Ming Ni ◽

Min Wang ◽

Lingli Ding ◽

...

Keyword(s):

Mechanical Properties ◽

Biomechanical Testing ◽

Tendon Healing ◽

Tendon Injury ◽

Rna Seq ◽

Injury Model ◽

New Treatment ◽

Underlying Mechanisms ◽

And Control

Abstract Background Tendon is a major component of musculoskeletal system connecting the muscles to the bone. Tendon injuries are very common orthopedics problems leading to impeded motion. Up to now, there still lacks effective treatments for tendon diseases. Methods Tendon stem/progenitor cells (TSPCs) were isolated from the patellar tendons of SD rats. The expression levels of genes were evaluated by quantitative RT-PCR. Immunohistochemistry staining was performed to confirm the presence of tendon markers in tendon tissues. Bioinformatics analysis of data acquired by RNA-seq was used to find out the differentially expressed genes. Rat patellar tendon injury model was used to evaluate the effect of U0126 on tendon injury healing. Biomechanical testing was applied to evaluate the mechanical properties of newly formed tendon tissues. Results In this study, we have shown that ERK inhibitor U0126 rather PD98059 could effectively increase the expression of tendon-related genes and promote the tenogenesis of TSPCs in vitro. To explore the underlying mechanisms, RNA sequencing was performed to identify the molecular difference between U0126-treated and control TSPCs. The result showed that GDF6 was significantly increased by U0126, which is an important factor of the TGFβ superfamily regulating tendon development and tenogenesis. In addition, NBM (nonwoven-based gelatin/polycaprolactone membrane) which mimics the native microenvironment of the tendon tissue was used as an acellular scaffold to carry U0126. The results demonstrated that when NBM was used in combination with U0126, tendon healing was significantly promoted with better histological staining outcomes and mechanical properties. Conclusion Taken together, we have found U0126 promoted tenogenesis in TSPCs through activating GDF6, and NBM loaded with U0126 significantly promoted tendon defect healing, which provides a new treatment for tendon injury.

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Autologous platelet rich plasma for regeneration of tendon injuries in horses

Indian Journal of Animal Research ◽

10.18805/ijar.b-3653 ◽

2019 ◽

Author(s):

S.Tina Roshini ◽

A. Arunprasad ◽

B.Justin William ◽

K. Jeyaraja ◽

K. Priyadharshini

Keyword(s):

Platelet Rich Plasma ◽

Tendon Healing ◽

Collagen Scaffold ◽

Economic Loss ◽

Tendon Injuries ◽

Flexor Tendon Injuries ◽

Healing Tendon ◽

Autologous Platelet Rich Plasma ◽

Autologous Platelet

Digital flexor tendon injuries are the most common cause of early retirement and economic loss in the equine industry due to the poor healing tendency of the tendons. This study was conducted to improve the quality of tendon healing by using Autologous Platelet Rich Plasma incorporated collagen scaffold. Using ultrasound guidance, autologous Platelet Rich Plasma with and without collagen scaffold was engrafted intra-lesionally into 12 affected digital flexor tendons of 11 horses and healing was assessed periodically. Lameness score decreased in all the horses and the therapeutic outcome of intra-lesional engraftment of Autologous Platelet Rich Plasma with collagen scaffold was found to be superior in terms of clinical outcome, ultrasonographic and biochemical assessment. Ultrasonography served as an effective tool for diagnosis and for evaluation of healing tendon injuries.

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Therapeutic Mechanisms of Human Adipose-Derived Mesenchymal Stem Cells in a Rat Tendon Injury Model

The American Journal of Sports Medicine ◽

10.1177/0363546517689874 ◽

2017 ◽

Vol 45 (6) ◽

pp. 1429-1439 ◽

Cited By ~ 29

Author(s):

Sang Yoon Lee ◽

Bomi Kwon ◽

Kyoungbun Lee ◽

Young Hoon Son ◽

Sun G. Chung

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Tendon Healing ◽

Collagen Type I ◽

Tendon Injury ◽

Cell Group ◽

Type I ◽

Injury Model ◽

Human Specific

Background: Although survival of transplanted stem cells in vivo and differentiation of stem cells into tenocytes in vitro have been reported, there have been no in vivo studies demonstrating that mesenchymal stem cells (MSCs) could secrete their own proteins as differentiated tenogenic cells. Purpose/Hypothesis: Using a xenogeneic MSC transplantation model, we aimed to investigate whether MSCs could differentiate into the tenogenic lineage and secrete their own proteins. The hypothesis was that human MSCs would differentiate into the human tenogenic lineage and the cells would be able to secrete human-specific proteins in a rat tendon injury model. Study Design: Controlled laboratory study. Methods: The Achilles tendons of 57 Sprague Dawley rats received full-thickness rectangular defects. After the modeling, the defective tendons were randomly assigned to 3 groups: (1) cell group, implantation with human adipose-derived mesenchymal stem cells (hASCs) and fibrin glue (106 cells in 60 μL); (2) fibrin group, implantation with fibrin glue and same volume of cell media; and (3) sham group, identical surgical procedure without any treatment. Gross observation and biomechanical, histopathological, immunohistochemistry, and Western blot analyses were performed at 2 and 4 weeks after modeling. Results: hASCs implanted into the defective rat tendons were viable for 4 weeks as detected by immunofluorescence staining. Tendons treated with hASCs showed better gross morphological and biomechanical recovery than those in the fibrin and sham groups. Furthermore, the expression of both human-specific collagen type I and tenascin-C was significantly higher in the cell group than in the other 2 groups. Conclusion: Transplantation of hASCs enhanced rat tendon healing biomechanically. hASCs implanted into the rat tendon defect model survived for at least 4 weeks and secreted human-specific collagen type I and tenascin-C. These findings suggest that transplanted MSCs may be able to differentiate into the tenogenic lineage and contribute their own proteins to tendon healing. Clinical Relevance: In tendon injury, MSCs can enhance tendon healing by secreting their own protein and have potential as a therapeutic option in human tendinopathy.

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The effect of tendon stem/progenitor cell (TSC) sheet on the early tendon healing in a rat Achilles tendon injury model

Acta Biomaterialia ◽

10.1016/j.actbio.2016.06.026 ◽

2016 ◽

Vol 42 ◽

pp. 136-146 ◽

Cited By ~ 24

Author(s):

Issei Komatsu ◽

James H-C. Wang ◽

Kiyotaka Iwasaki ◽

Tatsuya Shimizu ◽

Teruo Okano

Keyword(s):

Achilles Tendon ◽

Progenitor Cell ◽

Tendon Healing ◽

Tendon Injury ◽

Injury Model

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CD146 Delineates an Interfascicular Cell Sub-Population in Tendon That Is Recruited during Injury through Its Ligand Laminin-α4

International Journal of Molecular Sciences ◽

10.3390/ijms22189729 ◽

2021 ◽

Vol 22 (18) ◽

pp. 9729

Author(s):

Neil Marr ◽

Richard Meeson ◽

Elizabeth F. Kelly ◽

Yongxiang Fang ◽

Mandy J. Peffers ◽

...

Keyword(s):

Expression Patterns ◽

Tendon Repair ◽

Tendon Healing ◽

Tendon Injury ◽

Focal Lesion ◽

Post Injury ◽

Surface Receptors ◽

Basement Membrane Protein ◽

Injury Model ◽

Cell Niche

The interfascicular matrix (IFM) binds tendon fascicles and contains a population of morphologically distinct cells. However, the role of IFM-localised cell populations in tendon repair remains to be determined. The basement membrane protein laminin-α4 also localises to the IFM. Laminin-α4 is a ligand for several cell surface receptors, including CD146, a marker of pericyte and progenitor cells. We used a needle injury model in the rat Achilles tendon to test the hypothesis that the IFM is a niche for CD146+ cells that are mobilised in response to tendon damage. We also aimed to establish how expression patterns of circulating non-coding RNAs alter with tendon injury and identify potential RNA-based markers of tendon disease. The results demonstrate the formation of a focal lesion at the injury site, which increased in size and cellularity for up to 21 days post injury. In healthy tendon, CD146+ cells localised to the IFM, compared with injury, where CD146+ cells migrated towards the lesion at days 4 and 7, and populated the lesion 21 days post injury. This was accompanied by increased laminin-α4, suggesting that laminin-α4 facilitates CD146+ cell recruitment at injury sites. We also identified a panel of circulating microRNAs that are dysregulated with tendon injury. We propose that the IFM cell niche mediates the intrinsic response to injury, whereby an injury stimulus induces CD146+ cell migration. Further work is required to fully characterise CD146+ subpopulations within the IFM and establish their precise roles during tendon healing.

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Basic Research on Tendon Repair: Strategies, Evaluation, and Development

Frontiers in Medicine ◽

10.3389/fmed.2021.664909 ◽

2021 ◽

Vol 8 ◽

Author(s):

Zhi Jie Li ◽

Qian Qian Yang ◽

You Lang Zhou

Keyword(s):

Wound Healing ◽

Platelet Rich Plasma ◽

Healing Process ◽

Tendon Repair ◽

Continuous Optimization ◽

Tendon Healing ◽

Basic Research ◽

Clinical Problem ◽

Tendon Injury ◽

Wound Healing Process

Tendon is a fibro-elastic structure that links muscle and bone. Tendon injury can be divided into two types, chronic and acute. Each type of injury or degeneration can cause substantial pain and the loss of tendon function. The natural healing process of tendon injury is complex. According to the anatomical position of tendon tissue, the clinical results are different. The wound healing process includes three overlapping stages: wound healing, proliferation and tissue remodeling. Besides, the healing tendon also faces a high re-tear rate. Faced with the above difficulties, management of tendon injuries remains a clinical problem and needs to be solved urgently. In recent years, there are many new directions and advances in tendon healing. This review introduces tendon injury and sums up the development of tendon healing in recent years, including gene therapy, stem cell therapy, Platelet-rich plasma (PRP) therapy, growth factor and drug therapy and tissue engineering. Although most of these therapies have not yet developed to mature clinical application stage, with the repeated verification by researchers and continuous optimization of curative effect, that day will not be too far away.

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