TY - JOUR
AU - Atkinson, Stuart P.
AB - Viral infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lead to the development of coronavirus disease 2019 (COVID-19), and while many infected individuals fail to develop noticeable symptoms and others develop mild to moderate symptoms, a significant proportion develop severe or critical symptoms (with the latter including respiratory failure, shock, or multiorgan dysfunction) that can end in patient death. SARS-CoV-2 predominantly infects cells of the respiratory system,1 employing the angiotensin-converting enzyme 2 (ACE2) receptor as a means of entry2; however, the expression of ACE2 in multiple cell types in multiple tissues makes them highly susceptible to SARS-CoV-2 infection, which may explain, in part, the impact on multiple organ systems in COVID-19 patients. Viral replication within infected cells prompts apoptosis and the release of pro-inflammatory cytokines,3 which can induce a cytokine storm that prompts the development of acute respiratory distress syndrome, multiorgan failure, and death.4 Beyond supportive care for severely affected patients, we generally lack adequate treatment options; furthermore, we also lack faithful model systems to explore the SARS-CoV-2 lifecycle and evaluate the efficacy of potential stem cell therapeutics. In the first of our Featured Articles published this month in Stem Cells, Djidrovski et al describe the ability of SARS-CoV-2 to infect an induced pluripotent stem cell (iPSC)-derived airway model system in a study that may pave the way for broader and reproducible studies of viral airway infection.5 In a Related Article published recently in Stem Cells Translational Medicine, Desterke et al explored the expression of the ACE2 receptor (used for SARs-CoV-2 entry) in mesenchymal stem cells (MSCs) to assess their safety and potential as anti-inflammatory therapies for severe COVID-19 patients.6 The interaction of the 40-kDa type 1 transmembrane protein programmed death-ligand 1 (PD-L1) with programmed cell death protein 1 (PD1), a receptor expressed on the surface of T and B cells, modulates the immune system to promote self-tolerance. The binding of PD-L1 to PD-1 produces an inhibitory signal that reduces the proliferation/prompts the apoptosis of antigen-specific T cells and reduces the apoptosis of anti-inflammatory regulatory T cells. While the PD1/PD-L1 axis efficiently prevents the development of various autoimmune diseases, the proper function of this regulatory mechanism also prevents the immune system from targeting and destroying cancer cells.7 While the modulation of the PD-1/PD-L1 axis represents an exciting means of improving cancer treatments, we currently lack a broad understanding of the observed heterogeneous expression/activity in tumors, as exemplified in melanoma.8 Recent related research has also established that PD-L1 expression supports the engraftment of embryonic stem cell (ESC)-derived cells9 and promotes transplant tolerance.10 Overall, a range of recent studies has suggested the need for a more in-depth appreciation of the PD1/PD-L1 axis in areas including cancer research and stem cell therapeutic development. In the second of our Featured Articles published this month in Stem Cells, Kuo et al describe how crosstalk between sex-determining region Y-box 2 (SOX2)-mediated epigenetic programming and cytokine signaling impacts PD-L1 expression during ESC differentiation and cancer cell plasticity.11 In a Related Article published recently in Stem Cells Translational Medicine, Fang et al revealed that muscle stem cells (MuSCs) endow maturing macrophages with anti-inflammatory properties (including the increased expression of PD-L1) through the insulin-like growth factor-2 (IGF2)-mediated modulation of macrophage metabolism.12 FEATURED ARTICLES iPSC-Derived Upper Airway Model Provides Boost for COVID-19 Research Primary pulmonary epithelial cells grown at an air-liquid interface form a pseudostratified airway epithelium comprising all relevant airway epithelial cell types, and this in vitro model of the human airway has been employed in SARS-CoV-2/COVID-19-related studies.13 Importantly, the generation of airway epithelial cell types via the directed differentiation of human iPSCs can overcome limitations associated with primary cells and provide the enormous number of cells required for large-scale investigations. A recent Stem Cells article from researchers led by Lyle Armstrong (Newcastle University, Newcastle upon Tyne, UK) reports on the implementation of basal-like cells isolated from differentiating iPSCs in the generation of airway epithelial equivalents that can be infected by SARS-CoV-2.5 Djidrovski et al cultured iPSC-derived basal-like cells isolated from a mixed population of lung progenitors as a monolayer exposed to an air-liquid interface, which induced their differentiation and the formation of a pseudostratified epithelial construct that displayed similarities to the human upper airway epithelium. The upper airway epithelium constructs contained the required cell types (which secrete mucus and produce functional cilia) and, encouragingly, supported in vivo-like SARS-CoV-2 infection/replication (as evidenced by the release of virions into the growth media and the presence of the SARS-CoV-2 spike protein in specific cells) and inflammatory cytokine secretion at an in vivo- and disease-relevant level. Overall, the authors hope that their simple and scalable iPSC-based model may provide a straightforward means to develop therapies for respiratory viral infections and assess drug toxicity in the human lungs. Open in new tabDownload slide Open in new tabDownload slide https://doi.org/10.1002/stem.3422 Study of PD-L1 Regulation may Prompt Improved Cancer Immunotherapeutic Approaches In a recent Stem Cells article, researchers from the laboratories of Shih-Hwa Chiou (Taipei Veterans General Hospital) and Yu-Ting Chou (National Tsing Hua University, Taiwan, China) describe how crosstalk between epigenetic programming mediated by the SOX2 transcription factor14 and cytokine stimulation regulates PD-L1 expression in two experimental systems: ESC self-renewal/differentiation and cancer cell plasticity.11 Initial studies by the authors revealed upregulated PD-L1 expression during ESC differentiation accompanied by the formation of a permissive chromatin environment at the PD-L1 promoter mediated through histone deacetylase 1 activity. Meanwhile, the generation of iPSCs from fibroblasts (involving the expression of SOX215) was accompanied by the downregulated expression of PD-L1, epidermal growth factor receptor (EGFR), and its ligand heparin-binding EGF-like growth factor (HBEGF). Subsequent studies demonstrated that high SOX2 expression in lung cancer cells modulated plasticity and inhibited PD-L1, EGFR, and HBEGF expression16; however, the transition to SOX2-negative lung cancer cells prompted the formation of a permissive chromatin environment at the PD-L1 promoter similarly to the ESC model (thereby upregulating PD-L1 expression), while the HBEGF-mediated activation of EGFR signaling upregulated PD-L1 expression. Overall, the authors describe how SOX2 and cytokine signaling regulate PD-L1 expression levels during cancer cell plasticity and in ESCs, which may foster the development of enhanced PD-L1-mediated cancer immunotherapeutics and regenerative therapies. Open in new tabDownload slide Open in new tabDownload slide https://doi.org/10.1002/stem.3429 RELATED ARTICLES Evaluating the Applicability of MSCs as a COVID-19 Treatment Previous research led by Ali G. Turhan (University Paris Saclay, Villejuif, France) reported the ability of fetal MSCs to ameliorate the cytokine storm (as occurs in severe COVID-19 patients4) induced by ischemia-reperfusion injuries during experimental kidney transplantation.17 Their subsequent research aimed to evaluate a range of MSC types for their applicability to treat severe COVID-19 patients by comparing their expression of ACE2, a potential entry point for SARs-CoV-2 in transplanted MSCs. In a recent Stem Cells Translational Medicine article,6 Desterke et al reported on the bioinformatic and molecular analysis of MSCs from adult tissue, fetal tissue, and pluripotent stem cell origins with respect to the expression of both ACE2 and those signaling pathways associated with anti-inflammatory activity. The authors discovered that adult bone marrow, adipose tissue, and umbilical cord-derived MSCs expressed ACE2 at a relatively high level; however, early passage placenta-derived MSCs and MSCs derived from human ESCs/iPSCs expressed much lower levels of ACE2, providing evidence for their safe implementation as stem cell treatments for severe COVID-19 patients. Importantly, the use of pluripotent stem cell-derived MSCs will facilitate the generation of the enormous numbers of MSCs required for therapeutic applications. Interestingly, the authors also linked the existence of an anti-inflammatory transcriptional signature with low ACE2 expression in placenta-derived MSCs, providing further support for their application as a COVID-19 treatment. Overall, the authors hoped that their findings would guide the elaboration of MSC-based stem cell therapies for severe COVID-19 patients. Open in new tabDownload slide Open in new tabDownload slide https://doi.org/10.1002/sctm.20-0189 MuSC-Macrophage Interactions Boost Anti-Inflammatory Activity in Mouse Inflammatory Bowel Disease Model In their recent Stem Cells Translational Medicine article,12 researchers from the laboratories of Changshun Shao and Yufang Shi (Soochow University, Suzhou, Jiangsu, China) sought to explore how MuSCs modulate macrophage metabolism18 and improve anti-inflammatory function in the hope of creating enhanced therapies for conditions such as inflammatory bowel disease (IBD). Overall, Fang and Zhang et al. discovered that MuSC-derived IGF2 improves the anti-inflammatory properties of macrophages, including increased PD-L1 expression, by impacting their metabolic preferences. The authors first demonstrated that both MuSCs and MuSC-conditioned media effectively suppressed inflammation when infused into a mouse model of IBD; however, this effect disappeared following the depletion of macrophages. In vitro analysis demonstrated that the MuSC secretome boosted PD-L1 levels and reduced pro-inflammatory cytokine levels in macrophages treated with pro-inflammatory stimuli. Interestingly, the elevated levels of MuSC-secreted IGF2 elicited a specific effect on macrophages: this growth factor induced a metabolic switch toward oxidative phosphorylation at the expense of glycolysis, which polarized the macrophages into an anti-inflammatory state that supports tissue repair and regeneration. The relative importance of IGF2 was underlined in vivo, where the knockdown of IGF2 or IGF2 neutralization in MuSCs blocked the therapeutic effect of administered MuSCs in mice with IBD. Overall, these interesting findings support the implementation of MuSCs as part of improved therapies for inflammatory diseases, given that MuSCs secrete significantly higher levels of IGF2 than MSCs.19 Open in new tabDownload slide Open in new tabDownload slide https://doi.org/10.1002/sctm.19-0447 REFERENCES 1 Fu Y , Cheng Y , Wu Y . Understanding SARS-CoV-2-mediated inflammatory responses: from mechanisms to potential therapeutic tools . Virol Sin . 2020 ; 35 : 266 - 271 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Zhou P , Yang X-L , Wang X-G , et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin . Nature . 2020 ; 579 : 270 - 273 . Google Scholar Crossref Search ADS PubMed WorldCat 3 Sarzi-Puttini P , Giorgi V , Sirotti S , et al. COVID-19, cytokines and immunosuppression: what can we learn from severe acute respiratory syndrome? Clin Exp Rheumatol . 2020 ; 38 : 337 - 342 . Google Scholar PubMed OpenURL Placeholder Text WorldCat 4 Huang C , Wang Y , Li X , et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China . Lancet . 2020 ; 395 : 497 - 506 . Google Scholar Crossref Search ADS PubMed WorldCat 5 Djidrovski I , Georgiou M , Hughes GL , et al. SARS-CoV-2 infects an upper airway model derived from induced pluripotent stem cells . Stem Cells . 2021 ; 39 : 1310 - 1321 . Google Scholar Crossref Search ADS PubMed WorldCat 6 Desterke C , Griscelli F , Imeri J , et al. Molecular investigation of adequate sources of mesenchymal stem cells for cell therapy of COVID-19-associated organ failure . Stem Cells Translational Medicine . 2021 ; 10 : 568 - 571 . Google Scholar Crossref Search ADS PubMed WorldCat 7 Sun C , Mezzadra R , Schumacher TN . Regulation and function of the PD-L1 checkpoint . Immunity . 2018 ; 48 : 434 - 452 . Google Scholar Crossref Search ADS PubMed WorldCat 8 Madore J , Vilain RE , Menzies AM , et al. PD-L1 expression in melanoma shows marked heterogeneity within and between patients: implications for anti-PD-1/PD-L1 clinical trials . Pigment Cell Melanoma Res . 2015 ; 28 : 245 - 253 . Google Scholar Crossref Search ADS PubMed WorldCat 9 Rong Z , Wang M , Hu Z , et al. An effective approach to prevent immune rejection of human ESC-derived allografts . Cell Stem Cell . 2014 ; 14 : 121 - 130 . Google Scholar Crossref Search ADS PubMed WorldCat 10 Tanaka K , Albin MJ , Yuan X , et al. PDL1 is required for peripheral transplantation tolerance and protection from chronic allograft rejection . J Immunol . 2007 ; 179 : 5204 - 5210 . Google Scholar Crossref Search ADS PubMed WorldCat 11 Kuo M-H , Chen P-Y , Yang Y-P , et al. Cytokine and epigenetic regulation of programmed death-ligand 1 in stem cell differentiation and cancer cell plasticity . Stem Cells . 2021 ; 39 : 1298 - 1309 . Google Scholar Crossref Search ADS PubMed WorldCat 12 Fang J , Zhang S , Liu Z , et al. Skeletal muscle stem cells confer maturing macrophages anti-inflammatory properties through insulin-like growth factor-2 . Stem Cells Translational Medicine . 2020 ; 9 : 773 - 785 . Google Scholar Crossref Search ADS PubMed WorldCat 13 Pizzorno A , Padey B , Julien T , et al. Characterization and treatment of SARS-CoV-2 in nasal and bronchial human airway epithelia . Cell Rep Med . 2020 ; 1 :100059. Google Scholar OpenURL Placeholder Text WorldCat 14 Fong H , Hohenstein KA , Donovan PJ . Regulation of self-renewal and pluripotency by Sox2 in human embryonic stem cells . Stem Cells . 2008 ; 26 : 1931 - 1938 . Google Scholar Crossref Search ADS PubMed WorldCat 15 Takahashi K , Yamanaka S . Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors . Cell . 2006 ; 126 : 663 - 676 . Google Scholar Crossref Search ADS PubMed WorldCat 16 Lu Y , Futtner C , Rock JR , et al. Evidence that SOX2 overexpression is oncogenic in the lung . PLoS One . 2010 ; 5 :e11022. Google Scholar OpenURL Placeholder Text WorldCat 17 Baulier E , Favreau F , Le Corf A , et al. Amniotic fluid-derived mesenchymal stem cells prevent fibrosis and preserve renal function in a preclinical porcine model of kidney transplantation . Stem Cells Transl Med . 2014 ; 3 : 809 - 820 . Google Scholar Crossref Search ADS PubMed WorldCat 18 Kelly B , O'Neill LAJ . Metabolic reprogramming in macrophages and dendritic cells in innate immunity . Cell Res . 2015 ; 25 : 771 - 784 . Google Scholar Crossref Search ADS PubMed WorldCat 19 Charville GW , Cheung TH , Yoo B , et al. Ex vivo expansion and in vivo self-renewal of human muscle stem cells . Stem Cell Rep . 2015 ; 5 : 621 - 632 . Google Scholar Crossref Search ADS WorldCat Author notes Previews highlight research articles published in the current issue of Stem Cells, putting the results in context for readers. ©AlphaMed Press 2021 This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
TI - A Preview of Selected Articles
JF - Stem Cells
DO - 10.1002/stem.3451
DA - 2021-10-01
UR - https://www.deepdyve.com/lp/oxford-university-press/a-preview-of-selected-articles-t9pXM2SXNh
SP - 1285
EP - 1288
VL - 39
IS - 10
DP - DeepDyve
ER -