CCL2 and CXCL12 Derived from Mesenchymal Stromal Cells Cooperatively Polarize IL-10+ Tissue Macrophages to Mitigate Gut Injury

Giri, Jayeeta; Das, Rahul; Nylen, Emily; Chinnadurai, Raghavan; Galipeau, Jacques

doi:10.1016/j.celrep.2020.01.047

Cited by 126 publications

(121 citation statements)

References 57 publications

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“…This would make IV applications of MSCs a contraindication in COVID-19. Intramuscular injection of PLX-PAD was chosen because of longer in vivo survival of the cells, improved functionality, and a lack of hemocompatibility issues ( 18 , 34 , 42 – 45 ). Mode of delivery has a significant impact on the therapeutic activity of MSCs ( 45 ).…”

Section: Discussionmentioning

confidence: 99%

“…Intramuscular injection of PLX-PAD was chosen because of longer in vivo survival of the cells, improved functionality, and a lack of hemocompatibility issues ( 18 , 34 , 42 – 45 ). Mode of delivery has a significant impact on the therapeutic activity of MSCs ( 45 ). Intramuscular delivery potentiates the dwell time of MSCs due to the favorable in vivo milieu ( 34 , 42 , 44 ).…”

Section: Discussionmentioning

confidence: 99%

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Placenta-Derived Cell Therapy to Treat Patients With Respiratory Failure Due to Coronavirus Disease 2019

Barkama

Mayo

Paz

et al. 2020

Critical Care Explorations

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Placenta-Derived Cell Therapy to Treat Patients With Respiratory Failure Due to Coronavirus Disease 2019

Barkama

Mayo

Paz

et al. 2020

Critical Care Explorations

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show abstract

“…Alternative routes of cell administration such as intramuscular (IM) injection are increasingly explored as alternatives to IV injection (Figure 2A, right) because of longer in vivo survival of the cells, improved functionality, and a lack of hemocompatibility issues (8, 57, 70-73). Galipeau et al found that potency is dependent on the route of cell delivery, cell viability, and immune match (57) and that the mode of delivery impacts strongly on MSCs' therapeutic activity (73). IM delivery potentiates the dwell time of MSCs due to the favorable in vivo milieu (8,70,72).…”

Section: Need For Hemocompatibility Testing Of IV Applied Cellular Thmentioning

confidence: 99%

“…Needs: The clinical cell product properties and mode of celldelivery should anticipate the specific patient needs under consideration of the target indication to be treated (e.g., anticipation of anticoagulation protocols/bleeding risk and IM application as an alternative to IV infusion, shown to result in longer cell survival in vivo, associated with prolonged secretory activities, and a lack of coagulation issues, which may be important in the treatment of COVID-19) (7,8,60,73).…”

Section: Updated Cell Therapy Routines Reflecting the Specific Patientmentioning

confidence: 99%

MSC Therapies for COVID-19: Importance of Patient Coagulopathy, Thromboprophylaxis, Cell Product Quality and Mode of Delivery for Treatment Safety and Efficacy

et al. 2020

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Numerous clinical trials of mesenchymal stromal/stem cells (MSCs) as a new treatment for coronavirus-induced disease (COVID-19) have been registered recently, most of them based on intravenous (IV) infusion. There is no approved effective therapy for COVID-19, but MSC therapies have shown first promise in the treatment of acute respiratory distress syndrome (ARDS) pneumonia, inflammation, and sepsis, which are among the leading causes of mortality in COVID-19 patients. Many of the critically ill COVID-19 patients are in a hypercoagulable procoagulant state and at high risk for disseminated intravascular coagulation, thromboembolism, and thrombotic multiorgan failure, another cause of high fatality. It is not yet clear whether IV infusion is a safe and effective route of MSC delivery in COVID-19, since MSC-based products express variable levels of highly procoagulant tissue factor (TF/CD142), compromising the cells' hemocompatibility and safety profile. Of concern, IV infusions of poorly characterized MSC products with unchecked (high) TF/CD142 expression could trigger blood clotting in COVID-19 and other vulnerable patient populations and further promote the risk for thromboembolism. In contrast, well-characterized products with robust manufacturing procedures and optimized modes of clinical delivery hold great promise for ameliorating COVID-19 by exerting their beneficial immunomodulatory effects, inducing tissue repair and organ protection. While the need for MSC therapy in COVID-19 is apparent, integrating both innate and adaptive immune compatibility testing into the current guidelines for cell, tissue, and organ transplantation is critical for safe and effective therapies. It is paramount to only use wellcharacterized, safe MSCs even in the most urgent and experimental treatments. We here propose three steps to mitigate the risk for these vulnerable patients: (1) updated Moll et al. MSC Therapies for COVID-19 clinical guidelines for cell and tissue transplantation, (2) updated minimal criteria for characterization of cellular therapeutics, and (3) updated cell therapy routines reflecting specific patient needs.

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“…In addition, macrophages generated in the presence of MV130-MSCs induced a lower proliferative response of T cells than their control counterparts ( Figure 4K). As recent studies have demonstrated that MSC-derived CCL2 is required for polarizing IL-10 + tissue macrophages (48)(49)(50), the effect of priming MSCs with MV130 on its production was studied. As shown in Figure 4L, CCL2 production was upregulated in MV130-primed MSCs at both mRNA and protein levels (Supplemental Figure S3C).…”

Section: Priming Mscs With Mv130 Promotes Their Immunomodulatory Featmentioning

confidence: 99%

Involvement of Mesenchymal Stem Cells in Oral Mucosal Bacterial Immunotherapy

et al. 2020

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Recent clinical observations indicate that bacterial vaccines induce cross-protection against infections produced by different microorganisms. MV130, a polyvalent bacterial sublingual preparation designed to prevent recurrent respiratory infectious diseases, reduces the infection rate in patients with recurrent respiratory tract infections. On the other hand, mesenchymal stem cells (MSCs) are key cell components that contribute to the maintenance of tissue homeostasis and exert both immunostimulatory and immunosuppressive functions. Herein, we study the effects of MV130 in human MSC functionality as a potential mechanism that contributes to its clinical benefits. We provide evidence that during MV130 sublingual immunization of mice, resident oral mucosa MSCs can take up MV130 components and their numbers remain unchanged after vaccination, in contrast to granulocytes that are recruited from extramucosal tissues. MSCs treated in vitro with MV130 show an increased viability without affecting their differentiation potential. In the short-term, MSC treatment with MV130 induces higher leukocyte recruitment and T cell expansion. In contrast, once T-cell activation is initiated, MV130 stimulation induces an up-regulated expression of immunosuppressor factors in MSCs. Accordingly, MV130-primed MSCs reduce T lymphocyte proliferation, induce the differentiation of dendritic cells with immunosuppressive features and favor M2-like macrophage polarization, thus counterbalancing the immune response. In addition, MSCs trained with MV130 undergo functional changes, enhancing their immunomodulatory response to a secondary stimulus. Finally, we show that MSCs are able to uptake, process and retain a reservoir of the TLR ligands derived from MV130 digestion which can be subsequently transferred to dendritic cells, an additional feature that also may be associated to trained immunity.

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CCL2 and CXCL12 Derived from Mesenchymal Stromal Cells Cooperatively Polarize IL-10+ Tissue Macrophages to Mitigate Gut Injury

Cited by 126 publications

References 57 publications

Placenta-Derived Cell Therapy to Treat Patients With Respiratory Failure Due to Coronavirus Disease 2019

Placenta-Derived Cell Therapy to Treat Patients With Respiratory Failure Due to Coronavirus Disease 2019

MSC Therapies for COVID-19: Importance of Patient Coagulopathy, Thromboprophylaxis, Cell Product Quality and Mode of Delivery for Treatment Safety and Efficacy

Involvement of Mesenchymal Stem Cells in Oral Mucosal Bacterial Immunotherapy

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