Mesenchymal stem cell–based tissue regeneration is governed by recipient T lymphocytes via IFN-γ and TNF-α

Liu, Yi; Wang, Lei; Kikuiri, Takashi; Akiyama, Kentaro; Chen, Chider; Xu, Xiao; Yang, Ruili; Chen, Wan Jun; Wang, Songlin; Shi, Songtao

doi:10.1038/nm.2542

Cited by 574 publications

(661 citation statements)

References 38 publications

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“…Bone marrow cells were flashed out from bone cavity of fe- murs and tibias with 2% heat-inactivated fetal bovine serum (FBS; Equitech-Bio, Kerrville, TX, USA) and cultured with α minimum essential medium (α-MEM, Invitrogen) supplemented with 20% FBS, 2 mM L-glutamine (Invitrogen), 55 μM 2-mercaptoethanol (Invitrogen), 100 U/ml penicillin, and 100 μg/ml streptomycin (Invitrogen), as previously reported [43].…”

Section: Isolation Of Mouse Bone Marrow Mscsmentioning

confidence: 99%

A subset of IL-17+ mesenchymal stem cells possesses anti-Candida albicans effect

et al. 2012

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Section: Isolation Of Mouse Bone Marrow Mscsmentioning

confidence: 99%

A subset of IL-17+ mesenchymal stem cells possesses anti-Candida albicans effect

et al. 2012

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“…However, largely because there are few data on mechanism, the role of IFNG is unclear as to whether it induces or inhibits differentiation in these cells (39,40). Now, with the data on the mechanism reported here, it is clear that IFNG is a potent checkpoint inhibitor of osteogenesis, and we can understand how it can function as a master regulator of differentiation for the many different stem cells that have IFNG receptors.…”

Section: Ifng Is a Primary Checkpoint For Cytokine-induced Odontoblasticmentioning

confidence: 84%

Interferon-γ is a master checkpoint regulator of cytokine-induced differentiation

Zha

Bucher

Nejatfard

et al. 2017

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

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Cytokines are protein mediators that are known to be involved in many biological processes, including cell growth, survival, inflammation, and development. To study their regulation, we generated a library of 209 different cytokines. This was used in a combinatorial format to study the effects of cytokines on each other, with particular reference to the control of differentiation. This study showed that IFN-γ is a master checkpoint regulator for many cytokines. It operates via an autocrine mechanism to elevate STAT1 and induce internalization of gp130, a common component of many heterodimeric cytokine receptors. This targeting of a receptor subunit that is common to all members of an otherwise diverse family solves the problem of how a master regulator can control so many diverse receptors. When one adds an autocrine mechanism, fine control at the level of individual cells is achieved.A s our understanding of physiology grows, we are increasingly aware of its Newtonian aspects in that for every action there is another reaction with opposite consequences (1). Irrespective of whether one thinks in terms of homeostasis, feedback loops, or checkpoints, we increasingly uncover molecular systems that, in terms of function, induce cells to move in opposite ways. For example, although immune T-cell activation is critical in controlling disease, one needs a checkpoint to guard against overactivity that could result in autoimmunity (2, 3).In addition to adding to our general knowledge of cellular physiology, detailed understanding of the molecular mechanisms of activation and checkpoint processes has important therapeutic implications. Such an understanding allows two separate entry points into the regulation of cellular events. Thus, if one wants to promote a cellular function, the same outcome can be achieved by either enhancing the effector or inhibiting the checkpoint pathways, usually by perturbing the molecules that initiate them.One of the most important physiological systems is the cytokine cascade (4). However, here, because the cascade contains large numbers of separate molecules, each operating through different receptors, simple models of regulation break down. While one can imagine that each cytokine is paired with a separate checkpoint system operating in an opposite direction, it seemed to us to be unlikely, if for no other reason than the economical use of genetic information. Given that one had large sets of related molecules with overlapping signal transduction mechanisms and pathways, it seemed more reasonable to assume that, depending on the circumstance, some members of the cytokine repertoire regulate other members of the repertoire. This differs from situations such as PD-1, where the checkpoint mechanistic cascade differs completely from the activation mechanism. By contrast, we propose that cytokine members of a family regulate each other by perturbing common molecular mechanisms. Thus, if gene action economy is proposed for a family, its hallmark should be that some of the same molecules used for...

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“…By grafting bone marrow MSCs subcutaneously in a mouse model, using hydroxyapatite tricalcium phosphate (HA-TCP) particles as a carrier, we confirmed that recipient T-cells inhibit MSC-based bone regeneration using the same mechanism observed in vitro. Based on this finding, we further applied systemic infusion of Tregs, or local administration of aspirin, to reduce IFN-γ and TNF-α concentration, and found that both methods can markedly alleviate IFN-γ/TNF-α-induced MSC apoptosis, thereby improving MSC-mediated subcutaneous bone formation (Liu et al, 2011). Furthermore, we showed that local aspirin treatment and systemic Treg infusion are able to significantly improve MSC-mediated calvarial bone repair via inhibition of IFN-γ and TNF-α levels (Liu et al, 2011).…”

Section: Lymphocytes Affect Msc Survival and Differentiationmentioning

confidence: 99%

“…Based on this finding, we further applied systemic infusion of Tregs, or local administration of aspirin, to reduce IFN-γ and TNF-α concentration, and found that both methods can markedly alleviate IFN-γ/TNF-α-induced MSC apoptosis, thereby improving MSC-mediated subcutaneous bone formation (Liu et al, 2011). Furthermore, we showed that local aspirin treatment and systemic Treg infusion are able to significantly improve MSC-mediated calvarial bone repair via inhibition of IFN-γ and TNF-α levels (Liu et al, 2011). Therefore, treatment with aspirin or Tregs may provide promising approaches for improving MSC-based tissue engineering (Fig.…”

Section: Lymphocytes Affect Msc Survival and Differentiationmentioning

confidence: 99%

Interplay between Mesenchymal Stem Cells and Lymphocytes

2012

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In addition to their potential for replacing damaged and diseased tissues by differentiating into tissuespecific cells, mesenchymal stem cells (MSCs) have been found to interact closely with immune cells, such as lymphocytes. In this review, we will discuss current research regarding the immunomodulatory properties of MSCs and the effects of lymphocytes on MSCs. We will suggest how these findings could be translated to potential clinical treatment. MSCs can regulate immune response by inducing activated T-cell apoptosis through the FAS ligand (FASL)/FAS-mediated death pathway via cell-cell contact, leading to up-regulation of regulatory T-cells (Tregs), which ultimately results in immune tolerance. Conversely, lymphocytes can impair survival and osteogenic differentiation of implanted MSCs by secreting the pro-inflammatory cytokines IFN-γ and TNF-α and/or through the FASL/FAS-mediated death pathway, thereby negatively affecting MSC-mediated tissue regeneration. One novel strategy to improve MSC-based tissue engineering involves the reduction of IFN-γ and TNF-α concentration by systemic infusion of Tregs or local application of aspirin. Further understanding of the mechanisms underlying the interplay between lymphocytes and MSCs may be helpful in the development of promising approaches to improve cell-based regenerative medicine and immune therapies.

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Mesenchymal stem cell–based tissue regeneration is governed by recipient T lymphocytes via IFN-γ and TNF-α

Cited by 574 publications

References 38 publications

A subset of IL-17+ mesenchymal stem cells possesses anti-Candida albicans effect

A subset of IL-17+ mesenchymal stem cells possesses anti-Candida albicans effect

Interferon-γ is a master checkpoint regulator of cytokine-induced differentiation

Interplay between Mesenchymal Stem Cells and Lymphocytes

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