TSG-6 Released from Intradermally Injected Mesenchymal Stem Cells Accelerates Wound Healing and Reduces Tissue Fibrosis in Murine Full-Thickness Skin Wounds

Qi, Yu; Jiang, Dongsheng; Sindrilaru, Anca; Stegemann, Agatha; Schatz, Susanne; Treiber, Nicolai; Rojewski, Markus; Schrezenmeier, Hubert; Beken, Seppe Vander; Wlaschek, Meinhard; Böhm, Markus; Seitz, Alexander; Scholz, N.; Dürselen, Lutz; Brinckmann, Jürgen; Ignatius, Anita; Scharffetter‐­Kochanek, Karin

doi:10.1038/jid.2013.328

Cited by 215 publications

(192 citation statements)

References 48 publications

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“…The increase in Arg-1 immunoreactivity in LPS-treated mice at 14 days postoperative localized almost exclusively to the fibrous tissue in the window defect, which was much more abundant in these animals compared with the control animals and most likely reflected the profibrotic effect of the M2a macrophage subset [3,[34][35][36]. Similar macrophage-induced increases in fibrous tissue formation leading to defective healing of skin wounds have been associated with LPS-induced systemic inflammation [37]. In addition to macrophages, mast cells have been implicated in the immune response to trauma in a mouse model of acute systemic inflammation [9].…”

Section: Discussionmentioning

confidence: 74%

Defective Bone Repair in C57Bl6 Mice With Acute Systemic Inflammation

Behrends

Hui

Gao

et al. 2017

Clinical Orthopaedics &Amp; Related Research

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Background Bone repair is initiated with a local inflammatory response to injury. The presence of systemic inflammation impairs bone healing and often leads to malunion, although the underlying mechanisms remain poorly defined. Our research objective was to use a mouse model of cortical bone repair to determine the effect of systemic inflammation on cells in the bone healing microenvironment. Question/Purposes (1) Does systemic inflammation, induced by lipopolysaccharide (LPS) administration affect the quantity and quality of regenerating bone in primary bone healing? (2) Does systemic inflammation alter vascularization and the number or activity of inflammatory cells, osteoblasts, and osteoclasts in the bone healing microenvironment? Methods Cortical defects were drilled in the femoral diaphysis of female and male C57BL/6 mice aged 5 to 9 months that were treated with daily systemic injections of LPS or physiologic saline as control for 7 days. Mice were euthanized at 1 week (Control, n = 7; LPS, n = 8), 2 weeks (Control, n = 7; LPS, n = 8), and 6 weeks (Control, n = 9; LPS, n = 8) after surgery. The quantity (bone volume per tissue volume [BV/TV]) and microarchitecture (trabecular separation and thickness, porosity) of bone in the defect were quantified with time using microCT. The presence or activity of vascular endothelial cells (CD34), macrophages (F4/80), osteoblasts (alkaline phosphatase [ALP]), and osteoclasts (tartrate-resistant acid phosphatase [TRAP]) were evaluated using histochemical analyses.The institution of one or more of the authors (JEH, PAM) has received, during the study period, funding from the Fonds de recherche Santé Québec. The remaining authors certify that neither he or she, nor a member of his or her immediate family, has funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article. Results Only one of eight defects was bridged completely 6 weeks after surgery in LPS-injected mouse bones compared with seven of nine defects in the control mouse bones (odds ratio [OR], 0.04; 95% CI, 0.003-0.560; p = 0.007). The decrease in cortical bone in LPS-treated mice was reflected in reduced BV/TV (21% ± 4% vs 39% ± 10%; p\0.01), increased trabecular separation (240 ± 36 lm vs 171 ± 29 lm; p \ 0.01), decreased trabecular thickness (81 ± 18 lm vs 110 ± 22 lm; p = 0.02), and porosity (79% ± 4% vs 60% ± 10%; p \ 0.01) at 6 weeks postoperative. Defective healing was accompanied by decreased CD34 (1.1 ± 0.6 vs 3.4 ± 0.9; p\0.01), ALP (1.9 ± 0.9 vs 6.1 ± 3.2; p = 0.03), and TRAP (3.3 ± 4.7 vs 7.2 ± 4.0; p = 0.01) activity, and increased F4/80 (13 ± 2.6 vs 6.8 ± 1.7; p \ 0.01) activity at 2 weeks postoperative. Conclusion The results indicate that LPS-induced systemic inflammation reduced the amount and impaired the quality of bone regenerated in mouse femurs. The effects were associated with impaired revascularization, decreased bone turnover by osteoblasts...

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Section: Discussionmentioning

confidence: 74%

Defective Bone Repair in C57Bl6 Mice With Acute Systemic Inflammation

Behrends

Hui

Gao

et al. 2017

Clinical Orthopaedics &Amp; Related Research

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“…In another study, it is hypothesised that injected MSC that are entrapped in the lung as emboli secrete the anti-inflammatory protein tumour necrosis factor alpha induced protine-6 (TSG-6) (Lee et al, 2009a). A role for indirect action of MSC on regenerative processes is further strengthened by the observation that knock-down of TSG-6 is sufficient to abolish the beneficial effect of MSC-injection in a variety of models (Danchuk et al, 2011;Lee et al, 2009a;Qi et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Systemic mesenchymal stem cell administration enhances bone formation in fracture repair but not load-induced bone formation

Rapp

Bindl²,

Heilmann³

et al. 2015

eCM

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Mesenchymal stem cells (MSC) were shown to support bone regeneration, when they were locally transplanted into poorly healing fractures. The benefit of systemic MSC transplantation is currently less evident. There is consensus that systemically applied MSC are recruited to the site of injury, but it is debated whether they actually support bone formation. Furthermore, the question arises as to whether circulating MSC are recruited only in case of injury or whether they also participate in mechanically induced bone formation.To answer these questions we injected green fluorescent protein (GFP)-labelled MSC into C57BL/6J mice, which were subjected either to a femur osteotomy or to noninvasive mechanical ulna loading to induce bone formation. We detected GFP-labelled MSC in the early (day 10) and late fracture callus (day 21) by immunohistochemistry. Stromal cell-derived factor 1 (SDF-1 or CXCL-12), a key chemokine for stem cell attraction, was strongly expressed by virtually all cells near the osteotomy -indicating that SDF-1 may mediate cell migration to the site of injury. We found no differences in SDF-1 expression between the groups. Micro-computed tomography (µCT) revealed significantly more bone in the callus of the MSC treated mice compared to untreated controls. The bending stiffness of callus was not significantly altered after MSCapplication. In contrast, we failed to detect GFP-labelled MSC in the ulna after non-invasive mechanical loading. Histomorphometry and µCT revealed a significant loadinduced increase in bone formation; however, no further increase was found after MSC administration. Concluding, our results suggest that systemically administered MSC are recruited and support bone formation only in case of injury but not in mechanically induced bone formation.

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“…MSCs promote angiogenesis and migration, and they have the ability to induce regeneration rather than fi brosis in the wound microenvironment [91][92][93] . In diabetic animal models, systemic or local injections, for example, of both MSCs promote angiogenesis and migration, and they have the ability to induce regeneration rather than fi brosis in the wound microenvironment.…”

Section: Challenges and Perspectives In The Treatment Of Chronic Wounmentioning

confidence: 99%

Pathogenesis of wound healing disorders in the elderly

Makrantonaki

Wlaschek

Scharffetter‐Kochanek

2017

J Deutsche Derma Gesell

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Summary The elderly constitute the age group most susceptible to wound healing disorders and chronic wounds, the most prevalent being venous leg ulcers, pressure ulcers, and diabetic foot ulcers. However, other age‐associated diseases should also be taken into consideration in the diagnostic workup of chronic wounds, and not be underestimated. A better understanding of the pathomechanisms involved in the wound healing process is of key importance in combatting the difficulties associated with the treatment of chronic wounds. In recent decades, considerable progress has been made in the development of pioneering therapeutic strategies for chronic wounds. In this context, the use of growth factors and cytokines, tissue engineering, and cell therapy – including stem cells – have proven very promising. Nevertheless, prior to their introduction into routine clinical practice, large controlled clinical trials are required to assess the safety of these techniques.

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TSG-6 Released from Intradermally Injected Mesenchymal Stem Cells Accelerates Wound Healing and Reduces Tissue Fibrosis in Murine Full-Thickness Skin Wounds

Cited by 215 publications

References 48 publications

Defective Bone Repair in C57Bl6 Mice With Acute Systemic Inflammation

Defective Bone Repair in C57Bl6 Mice With Acute Systemic Inflammation

Systemic mesenchymal stem cell administration enhances bone formation in fracture repair but not load-induced bone formation

Pathogenesis of wound healing disorders in the elderly

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