Mesenchymal Stem Cells Suppress Severe Asthma by Directly Regulating Th2 Cells and Type 2 Innate Lymphoid Cells

Shin, Jae Woo; Ryu, Seungwon; Ham, Jongho; Jung, Keehoon; Lee, Sangho; Chung, Doo Hyun; Kang, Hye Ryun; Kim, Hye Young

doi:10.14348/molcells.2021.0101

Cited by 21 publications

(19 citation statements)

References 47 publications

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“…Pediatric severe asthma with fungal sensitization resulted in an increase in the number of IL-33-mediated ILC2s, Th2 cells, and steroid-resistant AHR [ 107 ]. Recently, it has been found that human umbilical cord blood-derived mesenchymal stem cells can also reduce lung type 2 (Th2 and ILC2s) inflammation [ 108 ]. Glucocorticoid is an effective drug for the treatment of asthma [ 109 ].…”

Section: Crosstalk Between Ilc2s and Cd4 + T Cells...mentioning

confidence: 99%

Crosstalk between ILC2s and Th2 CD4+ T Cells in Lung Disease

Guo

2022

Journal of Immunology Research

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Cytokine secretion, such as interleukin-4 (IL-4), IL-5, IL-9, IL-13, and amphiregulin (Areg), by type 2 innate lymphoid cells (ILC2s) is indispensable for homeostasis, remodeling/repairing tissue structure, inflammation, and tumor immunity. Often viewed as the innate cell surrogate of T helper type 2 (Th2) cells, ILC2s not only secrete the same type 2 cytokines, but are also inextricably related to CD4+T cells in terms of cell origin and regulatory factors, bridging between innate and adaptive immunity. ILC2s interact with CD4+T cells to play a leading role in a variety of diseases through secretory factors. Here, we review the latest progress on ILC2s and CD4+T cells in the lung, the close relationship between the two, and their relevance in the lung disease and immunity. This literature review aids future research in pulmonary type 2 immune diseases and guides innovative treatment approaches for these diseases.

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Section: Crosstalk Between Ilc2s and Cd4 + T Cells...mentioning

confidence: 99%

Crosstalk between ILC2s and Th2 CD4+ T Cells in Lung Disease

Guo

2022

Journal of Immunology Research

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“…MSCs also have the potential to transdifferentiate into ectodermal lineages (neurons and keratinocytes) ( Dos Santos et al, 2019 ; Poudineh et al, 2018 ) and endodermal lineages (hepatocytes and cardiomyocytes) ( Aurich et al, 2009 ; Sgodda et al, 2007 ; Szaraz et al, 2017 ). In addition to their differentiation potential into multiple lineages, MSCs have been considered as a cell-based drug to treat various neurological disorders, such as amyotrophic lateral sclerosis ( Mazzini et al, 2003 ; Suzuki et al, 2008 ), Parkinson’s disease ( Kan et al, 2007 ; Wang et al, 2010 ), Alzheimer’s disease ( Ma et al, 2013 ; Yang et al, 2013 ), stroke ( Lee et al, 2015 ; Xin et al, 2013 ), and non-neurological diseases, such as graft versus host diseases ( Le Blanc et al, 2004 ), myocardial infraction ( Huang et al, 2019 ), type 1 diabetes ( Unsal et al, 2015 ) and severe asthma ( Shin et al, 2021 ). More than 1,300 clinical trials are ongoing or have been completed worldwide using MSCs ( https://www.clinicaltrials.gov , with a query of “mesenchymal stem cells” 2021), indicating the broad application and usefulness of naive MSCs in cell-based drug development.…”

Section: Introductionmentioning

confidence: 99%

Improving the Safety of Mesenchymal Stem Cell-Based Ex Vivo Therapy Using Herpes Simplex Virus Thymidine Kinase

Bashyal

Lee²,

Chang³

et al. 2022

Molecules and Cells

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Human mesenchymal stem cells (MSCs) are multipotent stem cells that have been intensively studied as therapeutic tools for a variety of disorders. To enhance the efficacy of MSCs, therapeutic genes are introduced using retroviral and lentiviral vectors. However, serious adverse events (SAEs) such as tumorigenesis can be induced by insertional mutagenesis. We generated lentiviral vectors encoding the wild-type herpes simplex virus thymidine kinase (HSV-TK) gene and a gene containing a point mutation that results in an alanine to histidine substitution at residue 168 (TK(A168H)) and transduced expression in MSCs (MSC-TK and MSC-TK(A168H)). Transduction of lentiviral vectors encoding the TK(A168H) mutant did not alter the proliferation capacity, mesodermal differentiation potential, or surface antigenicity of MSCs. The MSC-TK(A168H) cells were genetically stable, as shown by karyotyping. MSC-TK(A168H) responded to ganciclovir (GCV) with an half maximal inhibitory concentration (IC 50 ) value 10-fold less than that of MSC-TK. Because MSC-TK(A168H) cells were found to be non-tumorigenic, a U87-TK(A168H) subcutaneous tumor was used as a SAE-like condition and we evaluated the effect of valganciclovir (vGCV), an oral prodrug for GCV. U87-TK(A168H) tumors were more efficiently ablated by 200 mg/kg vGCV than U87-TK tumors. These results indicate that MSC-TK(A168H) cells appear to be pre-clinically safe for therapeutic use. We propose that genetic modification with HSV-TK(A168H) makes allogeneic MSC-based ex vivo therapy safer by eliminating transplanted cells during SAEs such as uncontrolled cell proliferation.

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“…ILC2s have been suggested as the innate counterpart of Th2 cells which play important roles in the development of asthma. The suppression of ILC2s by intravenous treatment with ucMSCs was also confirmed by using two different mouse models of severe asthma using Alternaria alternata and house dust mite/diesel exhaust particle 29 . Previous studies have reported that Treg upregluation may be the mechanism behind the inhibitory effects of intravenously administered ucMSCs on the Th2 response 22 .…”

Section: Discussionmentioning

confidence: 66%

Intratracheal administration of mesenchymal stem cells modulates lung macrophage polarization and exerts anti-asthmatic effects

Kang

Bang

et al. 2022

Sci Rep

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Mesenchymal stem cells (MSCs) possess immunomodulatory properties that have therapeutic potential for the treatment of inflammatory diseases. This study investigates the effects of direct MSC administration on asthmatic airways. Umbilical cord MSCs (ucMSCs) were intratracheally administered to six-week-old female BALB/c mice sensitized and challenged with ovalbumin; airway hyperresponsiveness (AHR), analyses of airway inflammatory cells, lung histology, flow cytometry, and quantitative real-time PCR were performed. Furthermore, ex vivo and in vitro experiments were performed to assess the effects of ucMSC on M2 activation. Intratracheally administered ucMSCs decreased degree of airway resistance and the number of inflammatory cells such as T helper 2 (Th2) cells, type 2 innate lymphoid cells (ILC2), and macrophages in the murine asthma model. Particularly, MHCII and CD86 expression diminished in dendritic cells and alveolar macrophages (AMs) following ucMSC treatment. SiglecF+CD11c+CD11b- AMs show a negative correlation with type II inflammatory cells including Th2 cells, ILC2, and eosinophils in asthmatic mice and were restored following intratracheal ucMSCs treatment. In addition, ucMSCs decreased the macrophage polarization to M2, particularly M2a. The expression levels of markers associated with M2 polarization and Th2 inflammation were also decreased. ucMSC reduced Il-12 and Tnfa expression as well as that of M2 markers such as Cd206 and Retnla ex vivo. Furthermore, the in vitro study using IL-4 treated macrophages confirmed that both direct and indirect MSC treatment significantly reduced the expression of Il-5 and Il-13. In conclusion, ucMSCs appear to suppress type II inflammation by regulating lung macrophages via soluble mediators.

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Mesenchymal Stem Cells Suppress Severe Asthma by Directly Regulating Th2 Cells and Type 2 Innate Lymphoid Cells

Cited by 21 publications

References 47 publications

Crosstalk between ILC2s and Th2 CD4+ T Cells in Lung Disease

Crosstalk between ILC2s and Th2 CD4+ T Cells in Lung Disease

Improving the Safety of Mesenchymal Stem Cell-Based Ex Vivo Therapy Using Herpes Simplex Virus Thymidine Kinase

Intratracheal administration of mesenchymal stem cells modulates lung macrophage polarization and exerts anti-asthmatic effects

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