TSG-6 as a biomarker to predict efficacy of human mesenchymal stem/progenitor cells (hMSCs) in modulating sterile inflammation in vivo

Lee, Ryang Hwa; Yu, Jian; Foskett, Andrea M.; Peltier, Grant; Reneau, John; Bazhanov, Nikolay; Oh, Joo Youn; Prockop, Darwin J.

doi:10.1073/pnas.1416121111

Cited by 167 publications

(184 citation statements)

References 38 publications

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“…Recently, observations by our group and others identified TSG-6 as being responsible for the beneficial effects of MSCs in the treatment of disease models of the heart (4), cornea (5,19,32), brain (33), lung (34), and pancreas (35). TSG-6 exerts its antiinflammatory actions through multiple mechanisms, one of which is the modulation of myeloid cells into a tolerogenic phenotype.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem/stromal cells precondition lung monocytes/macrophages to produce tolerance against allo- and autoimmunity in the eye

Lee

Jeong

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Intravenously administered mesenchymal stem/stromal cells (MSCs) engraft only transiently in recipients, but confer long-term therapeutic benefits in patients with immune disorders. This suggests that MSCs induce immune tolerance by long-lasting effects on the recipient immune regulatory system. Here, we demonstrate that i.v. infusion of MSCs preconditioned lung monocytes/macrophages toward an immune regulatory phenotype in a TNF-α-stimulated gene/protein (TSG)-6-dependent manner. As a result, mice were protected against subsequent immune challenge in two models of alloand autoimmune ocular inflammation: corneal allotransplantation and experimental autoimmune uveitis (EAU). The monocytes/macrophages primed by MSCs expressed high levels of MHC class II, B220, CD11b, and IL-10, and exhibited T-cell-suppressive activities independently of FoxP3 + regulatory T cells. Adoptive transfer of MSCinduced B220 + CD11b + monocytes/macrophages prevented corneal allograft rejection and EAU. Deletion of monocytes/macrophages abrogated the MSC-induced tolerance. However, MSCs with TSG-6 knockdown did not induce MHC II + B220 + CD11b + cells, and failed to attenuate EAU. Therefore, the results demonstrate a mechanism of the MSC-mediated immune modulation through induction of innate immune tolerance that involves monocytes/macrophages. corneal allotransplantation | experimental autoimmune uveitis | immune tolerance | mesenchymal stem/stromal cell | monocyte/macrophage

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Section: Discussionmentioning

confidence: 99%

Mesenchymal stem/stromal cells precondition lung monocytes/macrophages to produce tolerance against allo- and autoimmunity in the eye

Lee

Jeong

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

136

109

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“…27,28 We, and others, have shown that hMSCs suppresses excessive sterile inflammation thereby ameliorating lung injury, 5 myocardial infarction, 29 corneal injury 30 or peritonitis, 26 in part due to hMSCs activation and secretion of TSG-6. Recently, Lee et al, 7 have proposed TSG-6 mRNA levels as a biomarker to predict in vivo efficacy in suppressing inflammation of different donor-derived hMSCs prior to use. Consistent with this concept, HCMV infection also inhibited secretion of IL-6 that is known to contribute to the antiinflammatory effects of ASCs in vivo, 6 possibly by inducing T-regulatory cells to secrete IL-10.…”

Section: Discussionmentioning

confidence: 99%

“…Data suggests that the therapeutic effects of ASCs are mediated in large part by release of paracrine factors that modulate inflammatory and immune responses or that enhance tissue repair. [5][6][7][8] Additionally, ASCs can differentiate into various tissues including fat, bone and cartilage 9 and thus have potential for regenerative stem cell therapies. 10,11 Despite promising therapeutic potential of ASCs, little is known about their susceptibility to infectious agents.…”

Section: Introductionmentioning

confidence: 99%

“…Results demonstrate that ASCs, as defined by the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cell Therapy (ISCT), 25 can be efficiently infected by HCMV and produce infectious HCMV progeny. Moreover, HCMV infection disrupts the adipogenic differentiation potential and upregulation of tumor necrosis factor-stimulated gene-6 protein (TSG-6), a proposed biomarker of immunomodulatory efficacy 7 and IL-6, a cytokine that has been shown to mediate many of the beneficial effects of ASCs. 6 Thus, HCMV infection significantly alters ASC function.…”

Section: Introductionmentioning

confidence: 99%

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Human cytomegalovirus infection of human adipose-derived stromal/stem cells restricts differentiation along the adipogenic lineage

et al. 2015

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Human adipose-derived stromal/stem cells (ASCs) display potential to be used in regenerative stem cell therapies and as treatments for inflammatory and autoimmune disorders. Despite promising use of ASCs as therapeutics, little is known about their susceptibility to infectious agents. In this study, we demonstrate that ASCs are highly susceptible to human cytomegalovirus (HCMV) infection and permissive for replication leading to release of infectious virions. Additionally, many basic ASC functions are inhibited during HCMV infection, such as differentiation and immunomodulatory potential. To our knowledge this is the first study examining potential adverse effects of HCMV infection on ASC biology. Our results suggest, that an active HCMV infection during ASC therapy may result in a poor clinical outcome due to interference by the virus.

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“…The group also showed that the expression level of TSG--6 mRNA could be directly correlated with MSC capacity to reduce inflammation in sterile mouse models of corneal injury, peritonitis, and lung injury [208]. In a type 1 diabetic mouse model, TSG--6 secreted by MSC was shown by others to inhibit the activation of antigen presenting cells, as well as T cells, and effectively delaying the onset of type 1 diabetes [209].…”

Section: Immune Modulatory Properties Of Mscmentioning

confidence: 96%

Device and application development for haematopoietic stem and progenitor cell (HSPC) and mesenchymal stromal cell (MSC) 3D spheroid cultures

Futrega¹

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KeywordsAIM 2: Utilization of the high throughput microwell platform to manufacture HSPC/MSC spheroids to improve the efficacy of direct BM transplantation.AIM 3: Development of an improved microwell platform that retains spheroids within discrete microwells throughout culture. AIM 4:Characterization of HSPC surface marker change in response to microwell material. DEVICE AND APPLICATION DEVELOPMENT FOR HSPC AND MSC 3D SPHEROID CULTURES iiiChapter 2 describes the development of a high throughput HSPC/MSC 3D spheroid co--culture embodied in AIM 1. I developed a high throughput polydimethylsiloxane (PDMS) microwell platform that enabled the manufacture of thousands of uniform 3D multicellular co--culture spheroids. Spheroids were assembled such that each contained 25--to--400 BM--derived MSC and 10 CB--derived CD34 + cells (a cell population enriched for HSPC). The outcomes from this Chapter guided the design of the subsequent three chapters. The specific outcomes and subsequent study results were as follows:Chapter 3: As described in Chapter 2, only modest improvements in expansion could be achieved by co--culturing HSPC in 3D MSC spheroids using a microwell platform. We reasoned that the 3D spheroids could, however, function as a biologically active anchor to improve direct BM transplantation outcomes. In this Chapter, we contrasted transplantation methods, including the use of MSC suspensions and 3D multicellular spheroids to modulate human CB--derived CD34 + cell retention within the BM cavity of NOD/SCID gamma (NSG) mice. Analysis revealed that the BM of injected femurs in some animals was saturated with human cells, while distal haematopoietic tissue engraftment was poor. These data show, for the first time, that retention of human haematopoietic cells within the BM enhances local engraftment at the expense of systemic engraftment.Chapter 4: As identified in Chapter 2, improvements in 3D spheroid co--cultures will require that the microwell platform is compatible with repeated medium exchange or dilution feeding. Multiple partial or complete medium exchanges can displace spheroids from discrete microwells, and this can result in either the loss of spheroids from culture, or spheroid amalgamation when displaced microtissues fall into common microwells. In this Chapter, I describe the first microwell platform that incorporates a mesh to retain microtissues within discrete microwells. We called this platform the microwell--mesh. We show that bonding a nylon mesh with an appropriate pore size over the microwell openings allows single cells to pass through the mesh into the microwells during the seeding process, but subsequently retains assembled microtissues within discrete microwells.Chapter 5: As identified in Chapter 2, the presence of PDMS, the material used to fabricate the microwell platform, altered CD38 surface expression on CB--derived CD34 + cells. Previous reports have shown that inhibition of retinoic acid signaling down--regulated CD38 iv DEVICE AND APPLICATION DEVELOPMENT FOR HSPC AND MSC 3D SPHE...

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TSG-6 as a biomarker to predict efficacy of human mesenchymal stem/progenitor cells (hMSCs) in modulating sterile inflammation in vivo

Cited by 167 publications

References 38 publications

Mesenchymal stem/stromal cells precondition lung monocytes/macrophages to produce tolerance against allo- and autoimmunity in the eye

Mesenchymal stem/stromal cells precondition lung monocytes/macrophages to produce tolerance against allo- and autoimmunity in the eye

Human cytomegalovirus infection of human adipose-derived stromal/stem cells restricts differentiation along the adipogenic lineage

Device and application development for haematopoietic stem and progenitor cell (HSPC) and mesenchymal stromal cell (MSC) 3D spheroid cultures

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