Identification and Modulation of Microenvironment Is Crucial for Effective Mesenchymal Stromal Cell Therapy in Acute Lung Injury

Islam, Diana; Huang, Yongbo; Fanelli, Vito; Delsedime, Luisa; Wu, Sulong; Khang, Julie; Han, Bing; Grassi, Alice; Li, Manshu; Xu, Yonghao; Luo, Alice; Wu, Jianfeng; Liu, Xiaoqing; McKillop, Montey; Medin, Jeffery A.; Qiu, Haibo; Zhong, Nanshan; Liu, Mingyao; Laffey, John G.; Li, Yimin; Zhang, Haibo

doi:10.1164/rccm.201802-0356oc

Cited by 100 publications

(116 citation statements)

References 48 publications

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“…TGFβ1 is also an important index of brosis and in ammation 28 . Despite this, pulmonary brosis in ARDS mice was also detected after MSCs transplantation 29 . According to Masson's staining or speci c mRNA expression, MSCs overexpressing TGFβ1 did not signi cantly increase pulmonary brosis in ARDS mice.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of TGFβ1 in murine mesenchymal stem cells improves lung inflammation by impacting the Th17/Treg balance in LPS-induced ARDS mice

Chen

Zhang

Xie

et al. 2020

Preprint

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Abstract Background: T helper 17 cells (Th17) /regulatory T cells (Treg), as subtypes of CD4 + T cells, play an important role in the inflammatory response of acute respiratory distress syndrome (ARDS). However, there is still a lack of effective methods to regulate the differentiation balance of Th17/Treg. It was proven that mesenchymal stem cells (MSCs) could regulate the differentiation of CD4 + T cells, but the mechanism is still unclear. TGFβ1, a paracrine cytokine of MSCs, could also regulate the differentiation of Th17/Treg but is lowly expressed in MSCs. Therefore, mouse MSCs (mMSCs) overexpressing TGFβ1 were constructed by lentivirus transfection and intratracheally transplanted into LPS-induced ARDS mice in our study. The aim of this study was to evaluate the therapeutic effects of mMSCs overexpressing TGFβ1 on inflammation and immunoregulation by impacting the Th17/Treg balance in LPS-induced ARDS mice. Methods: mMSCs overexpressing TGFβ1 were constructed using lentiviral vectors. Then, mouse bone-marrow-derived MSCs (mBM-MSC) and mBM-MSC-TGFβ1 (mBM-MSC overexpressing TGFβ1) were transplanted intratracheally into ARDS mice induced by lipopolysaccharide. At 3 d and 7 d after transplantation, the mice were sacrificed, and the homing of the mMSCs was assayed by ex vivo optical imaging. The relative numbers of Th17 and Treg in the lungs and spleens of mice were detected by FCM. IL-17A and IL-10 levels in the lungs of mice were analysed by western blot. Permeability and inflammatory cytokines were evaluated by analysing the protein concentration of BALF using ELISA. Histopathology of the lungs was assessed by haematoxylin and eosin staining and lung injury scoring. Alveolar lung fibrosis was assessed by Masson’s trichrome staining and Ashcroft scoring. The mortality of ARDS mice was followed until 7 days after transplantation. Results: The transduction efficiencies mediated by the lentiviral vectors ranged from 82.3-88.6%. Overexpressing TGF-β1 inhibited the proliferation of mMSCs during days 5-7 ( p <0.05) but had no effect on mMSCs differentiation or migration ( p >0.05). Compared to that in the LPS+mBM-MSC-NC group mice, engraftment of mMSCs overexpressing TGFβ1 led to much more differentiation of T cells into Th17 or Treg ( p <0.05), improved permeability of injured lungs ( p <0.05) and ameliorative histopathology of lung tissue in ARDS mice ( p <0.05). Moreover, IL-17A content was also decreased while IL-10 content was increased in the LPS+mBM-MSC-TGFβ1 group compared with those in the LPS+mBM-MSC-NC group ( p <0.05). Finally, mMSCs overexpressing TGFβ1 did not aggravate lung fibrosis in ARDS mice ( p >0.05). Conclusion: MSCs overexpressing TGFβ1 could regulate lung inflammation and attenuate lung injuries by modulating the imbalance of Th17/Treg in the lungs of ARDS mice.

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Section: Discussionmentioning

confidence: 99%

Overexpression of TGFβ1 in murine mesenchymal stem cells improves lung inflammation by impacting the Th17/Treg balance in LPS-induced ARDS mice

Chen

Zhang

Xie

et al. 2020

Preprint

Self Cite

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“…It should be appreciated that the lung microenvironment can profoundly influence the properties of MSCs and their beneficial effects on ARDS upon initiating MSC administration. 21 Previous study by Islam et al showed that stimulation of human MSCs with plasma of ARDS patients resulted in the decrease of CD105 and CD90 for 5 days, suggesting a phenotype shift. 21 This observation also suggests the need to consider whether ACE2 on MSC surface may be altered by the inflammatory environment.…”

Section: Potential Challenges For Msc-based Approaches For Covid-19mentioning

confidence: 96%

<p>Challenges for Mesenchymal Stem Cell-Based Therapy for COVID-19</p>

Li¹,

Zhao²,

Wang³

2020

DDDT

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The coronavirus disease 2019 (COVID-19) global pandemic continues and antiviral agents and vaccines are currently under investigation. Mesenchymal stem cell (MSC)-based therapy can be a suitable option for management of patients with COVID-19 at the urgent time of virus outbreak. Currently, MSCs are being explored against the novel infectious disease due to their therapeutic properties of anti-inflammation, immunomodulation and tissue repair and regeneration, albeit the precise mechanisms of MSC action toward COVID-19 remain unclear. To date, rigorous results from clinical trials using MSCs in human have been weakly positive. The pervasive uncertainty of using MSC therapeutic products as an effective combatant against COVID-19 requires rigorous resolution on several fronts, including MSC fate after infusion, safety issue, homing capability, and MSC resistance to the disease microenvironment. Focusing on these facets, a few important ones will be critically analyzed and addressed in this article for the development of safe and effective MSC-based therapies for COVID-19.

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“…J. Collins (Erasmus University Medical Center, Netherlands), discussed the involvement of the endogenous lung MSCs in pathological changes leading to BPD and the role of microbiome in shaping endogenous MSC populations. Indeed, accumulating evidence suggests that disease microenvironment can influence MSC behaviours and consequently therapeutic potential [ 9 , 80 , 81 ]. Therefore, a better understanding of the lung injury microenvironment and how it alters functional properties of the cell-based therapies is essential to their effective clinical translation and will be an important area of further investigation.…”

Section: Session VII Immunomodulation Via Cell Thmentioning

confidence: 99%

“…Understanding how cells or cellular derivatives, such as EVs or ECM, influence cell behaviour in the lung is central to designing cellular therapies for acute and chronic lung diseases. As previously discussed, MSCs have potential therapeutic benefit in the treatment of several lung diseases [ 5 , 9 , 72 ]. P ati and co-workers [ 82 , 83 ] (University of California San Francisco, USA) has shown that MSC actions are mediated by different effectors in different diseases.…”

Section: Session IX New Strategies For Cellular Delivery and Regenermentioning

confidence: 99%

Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Disease 2019

et al. 2020

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A workshop entitled “Stem Cells, Cell Therapies and Bioengineering in Lung Biology and Diseases” was hosted by the University of Vermont Larner College of Medicine in collaboration with the National Heart, Lung and Blood Institute, the Alpha-1 Foundation, the Cystic Fibrosis Foundation, the International Society for Cell and Gene Therapy and the Pulmonary Fibrosis Foundation. The event was held from July 15 to 18, 2019 at the University of Vermont, Burlington, Vermont. The objectives of the conference were to review and discuss the current status of the following active areas of research: 1) technological advancements in the analysis and visualisation of lung stem and progenitor cells; 2) evaluation of lung stem and progenitor cells in the context of their interactions with the niche; 3) progress toward the application and delivery of stem and progenitor cells for the treatment of lung diseases such as cystic fibrosis; 4) progress in induced pluripotent stem cell models and application for disease modelling; and 5) the emerging roles of cell therapy and extracellular vesicles in immunomodulation of the lung. This selection of topics represents some of the most dynamic research areas in which incredible progress continues to be made. The workshop also included active discussion on the regulation and commercialisation of regenerative medicine products and concluded with an open discussion to set priorities and recommendations for future research directions in basic and translation lung biology.

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Identification and Modulation of Microenvironment Is Crucial for Effective Mesenchymal Stromal Cell Therapy in Acute Lung Injury

Cited by 100 publications

References 48 publications

Overexpression of TGFβ1 in murine mesenchymal stem cells improves lung inflammation by impacting the Th17/Treg balance in LPS-induced ARDS mice

Overexpression of TGFβ1 in murine mesenchymal stem cells improves lung inflammation by impacting the Th17/Treg balance in LPS-induced ARDS mice

<p>Challenges for Mesenchymal Stem Cell-Based Therapy for COVID-19</p>

Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Disease 2019

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