Enhanced Medial Collateral Ligament Healing Using Mesenchymal Stem Cells: Dosage Effects on Cellular Response and Cytokine Profile

Saether, Erin E.; Chamberlain, Connie S.; Leiferman, Ellen M.; Kondratko-Mittnacht, Jaclyn; Li, Wan‐Ju; Brickson, Stacey; Vanderby, Ray

doi:10.1007/s12015-013-9479-7

Cited by 32 publications

(44 citation statements)

References 38 publications

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“…In addition, all low cell density treated explants demonstrated adhered MSCs to their surface, whereas this was not the case for the high cell density treatment. Although dose-dependent effects have been reported for allogeneic MSCs for the treatment of myocardial infarction in rats [38] and graft versus host disease in mice [39], others have also demonstrated a superior outcome using a lower density of allogeneic MSCs for treatment of injured medial collateral ligaments of rat knees [40] or for the treatment of human knee osteoarthritis [41]. As clump formation did not differ between the cell density groups, the difference was unlikely due to steric obstruction.…”

Section: Discussionmentioning

confidence: 95%

Chondrogenic Priming at Reduced Cell Density Enhances Cartilage Adhesion of Equine Allogeneic MSCs - a Loading Sensitive Phenomenon in an Organ Culture Study with 180 Explants

Spaas¹,

Broeckx²,

Chiers

et al. 2015

Cell Physiol Biochem

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Background: Clinical results of regenerative treatments for osteoarthritis are becoming increasingly significant. However, several questions remain unanswered concerning mesenchymal stem cell (MSC) adhesion and incorporation into cartilage. Methods: To this end, peripheral blood (PB) MSCs were chondrogenically induced and/or stimulated with pulsed electromagnetic fields (PEMFs) for a brief period of time just sufficient to prime differentiation. In an organ culture study, PKH26 labelled MSCs were added at two different cell densities (0.5 x10⁶ vs 1.0 x10⁶). In total, 180 explants of six horses (30 per horse) were divided into five groups: no lesion (i), lesion alone (ii), lesion with naïve MSCs (iii), lesion with chondrogenically-induced MSCs (iv) and lesion with chondrogenically-induced and PEMF-stimulated MSCs (v). Half of the explants were mechanically loaded and compared with the unloaded equivalents. Within each circumstance, six explants were histologically evaluated at different time points (day 1, 5 and 14). Results: COMP expression was selectively increased by chondrogenic induction (p = 0.0488). PEMF stimulation (1mT for 10 minutes) further augmented COL II expression over induced values (p = 0.0405). On the other hand, MSC markers remained constant over time after induction, indicating a largely predifferentiated state. In the unloaded group, MSCs adhered to the surface in 92.6% of the explants and penetrated into 40.7% of the lesions. On the other hand, physiological loading significantly reduced surface adherence (1.9%) and lesion filling (3.7%) in all the different conditions (p < 0.0001). Remarkably, homogenous cell distribution was characteristic for chondrogenic induced MSCs (+/- PEMFs), whereas clump formation occurred in 39% of uninduced MSC treated cartilage explants. Finally, unloaded explants seeded with a moderately low density of MSCs exhibited greater lesion filling (p = 0.0022) and surface adherence (p = 0.0161) than explants seeded with higher densities of MSCs. In all cases, the overall amount of lesion filling decreased from day 5 to 14 (p = 0.0156). Conclusion: The present study demonstrates that primed chondrogenic induction of MSCs at a lower cell density without loading results in significantly enhanced and homogenous MSC adhesion and incorporation into equine cartilage.

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Section: Discussionmentioning

confidence: 95%

Chondrogenic Priming at Reduced Cell Density Enhances Cartilage Adhesion of Equine Allogeneic MSCs - a Loading Sensitive Phenomenon in an Organ Culture Study with 180 Explants

Spaas¹,

Broeckx²,

Chiers

et al. 2015

Cell Physiol Biochem

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“…In vitro studies of macrophages co-cultured with bone marrow-derived MSCs produced high levels of the anti-inflammatory factors CD206 (a marker for M2 macrophages) and IL-10, as well as low levels of inflammatory cytokines IL-12 and TNF-α [8]. In vivo studies from our lab examined MSC-mediated immune modulation during ligament healing from a dose-dependent perspective [9]. Specifically, injured rat medial collateral ligaments (MCLs) were treated with either 1 × 10 6 (low dose) or 4 × 10 6 (high dose) allogeneic MSCs [9].…”

Section: Immunosuppressive Effects Of Mesenchymal Stem Cells On Muscumentioning

confidence: 99%

“…In vivo studies from our lab examined MSC-mediated immune modulation during ligament healing from a dose-dependent perspective [9]. Specifically, injured rat medial collateral ligaments (MCLs) were treated with either 1 × 10 6 (low dose) or 4 × 10 6 (high dose) allogeneic MSCs [9]. Within the early healing ligament, fewer M1 macrophages localized within the low dose group resulting in lower amounts of inflammatory cytokines (IL-1α, IL-12 and IFN-γ) than the high dose MSC group (Figure 2) [9].…”

Section: Immunosuppressive Effects Of Mesenchymal Stem Cells On Muscumentioning

confidence: 99%

“…Specifically, injured rat medial collateral ligaments (MCLs) were treated with either 1 × 10 6 (low dose) or 4 × 10 6 (high dose) allogeneic MSCs [9]. Within the early healing ligament, fewer M1 macrophages localized within the low dose group resulting in lower amounts of inflammatory cytokines (IL-1α, IL-12 and IFN-γ) than the high dose MSC group (Figure 2) [9]. The low dose group also increased failure strength and stiffness of the healing MCL, improving functional behavior.…”

Section: Immunosuppressive Effects Of Mesenchymal Stem Cells On Muscumentioning

confidence: 99%

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Mesenchymal Stem Cell Therapy on Tendon/Ligament Healing

et al. 2017

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A normal healing response after ligament and tendon rupture results in scar formation and an inferior tissue that fails to emulate its original structure, composition, and function. More regenerative healing (closer to the original) can be obtained through early suppression of inflammatory cells and associated cytokines. Examination of the immune mediated response of mesenchymal stem/stromal cells (MSCs) during healing indicates that MSCs reprogram macrophages from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype. Based on these studies our objective was to treat ligament and tendon injuries with MSCs in order to modulate their inflammatory response. Our initial studies using allogeneic cells demonstrated an in vivo dose dependency of MSCs on ligament healing. Medial collateral ligaments (MCLs) treated with 1 × 10 6 (low dose) MSCs exhibited less inflammation and a reduced number of M1 macrophages compared to ligaments treated with 4 × 10 6 (high dose) MSCs. Strength of ligament was also improved with the low dose treatment. We then examined the in vivo effects of MSCs that had been preconditioned to be more anti-inflammatory. Treatment with these preconditioned MSCs was compared with normally processed (unconditioned) MSCs using the rat Achilles tendon and MCL healing models. Pre-conditioned MSCs significantly reduced inflammation by increasing the M2 macrophages and decreasing the M1 macrophages. Most importantly, treatment with pre-conditioned MSCs improved tissue strength to levels comparable to intact tissue. Overall, pre-conditioned MSC-treatment out-performed unconditioned MSCs to improve ligament and tendon healing by stimulating a more robust, paracrine-mediated immunosuppressive response. Ligament and Tendon HealingAfter rupture, normal ligament and tendon healing undergoes inflammation, proliferation, and remodeling. During inflammation, neutrophils, M1 and M2 macrophages, and to a lesser degree, tlymphocytes infiltrate the wound. Fibroblasts, endothelial cells and additional macrophages accrue thereafter and form granulation tissue during proliferation. As healing progresses, production of type I procollagen decreases while type III collagen increases [1]. The newly formed type III collagen produces a weak transient connection for injured tissue. As remodeling continues, the ratio of type I to type III collagen improves along with the tensile strength of the compromised region, but nevertheless results in a mechanically inferior tissue that fails to mimic its original structure. An improved healing scenario would involve no scar formation, reduced inflammation, organized collagen fibers, restored concentrations of type I collagen, and mechanical function that mimics native tissue. Previous studies indicate that early suppression of inflammatory cells and associated cytokines promotes regenerative healing of tendons/ligaments towards their original structure [2][3][4]. Based on these studies our objective was to treat musculoskeletal injuries with MSCs which are known modul...

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“…Autologous adipose derived stem cells are sufficient in number to heal or regenerate the damaged tendons. Dosage effects on cellular responses and cytokine profiles have been reported [13] . Interestingly, the lower dose of cells proved to be more effective in improving functional properties.…”

Section: Tendon Regenerationmentioning

confidence: 99%

Orthopedic cellular therapy: An overview with focus on clinical trials

Noh¹

2015

WJO

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In this editorial, the authors tried to evaluate the present state of cellular therapy in orthopedic field. The topics the authors try to cover include not only the clinical trials but the various research areas as well. Both the target diseases for cellular therapy and the target cells were reviewed. New methods to activate the cells were interesting to review. Most advanced clinical trials were also included because several of them have advanced to phase Ⅲ clinical trials. In the orthopedic field, there are many diseases with a definite treatment gap at this time. Because cellular therapies can regenerate damaged tissues, there is a possibility for cellular therapies to become disease modifying drugs. It is not clear whether cellular therapies will become the standard of care in any of the orthopedic disorders, however the amount of research being performed and the number of clinical trials that are on-going make the authors believe that cellular therapies will become important treatment modalities within several years.

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Enhanced Medial Collateral Ligament Healing Using Mesenchymal Stem Cells: Dosage Effects on Cellular Response and Cytokine Profile

Cited by 32 publications

References 38 publications

Chondrogenic Priming at Reduced Cell Density Enhances Cartilage Adhesion of Equine Allogeneic MSCs - a Loading Sensitive Phenomenon in an Organ Culture Study with 180 Explants

Chondrogenic Priming at Reduced Cell Density Enhances Cartilage Adhesion of Equine Allogeneic MSCs - a Loading Sensitive Phenomenon in an Organ Culture Study with 180 Explants

Mesenchymal Stem Cell Therapy on Tendon/Ligament Healing

Orthopedic cellular therapy: An overview with focus on clinical trials

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