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1. Studying Heterotypic Cell–Cell Interactions in the Human Brain Using Pluripotent Stem Cell Models for Neurodegeneration

   https://doi.org/10.3390/cells8040299  

   Song, Liqing ; Yan, Yuanwei ; Marzano, Mark ; Li, Yan ( April 2019 , Cells)

   Human cerebral organoids derived from induced pluripotent stem cells (iPSCs) provide novel tools for recapitulating the cytoarchitecture of the human brain and for studying biological mechanisms of neurological disorders. However, the heterotypic interactions of neurovascular units, composed of neurons, pericytes (i.e., the tissue resident mesenchymal stromal cells), astrocytes, and brain microvascular endothelial cells, in brain-like tissues are less investigated. In addition, most cortical organoids lack a microglia component, the resident immune cells in the brain. Impairment of the blood-brain barrier caused by improper crosstalk between neural cells and vascular cells is associated with many neurodegenerative disorders. Mesenchymal stem cells (MSCs), with a phenotype overlapping with pericytes, have promotion effects on neurogenesis and angiogenesis, which are mainly attributed to secreted growth factors and extracellular matrices. As the innate macrophages of the central nervous system, microglia regulate neuronal activities and promote neuronal differentiation by secreting neurotrophic factors and pro-/anti-inflammatory molecules. Neuronal-microglia interactions mediated by chemokines signaling can be modulated in vitro for recapitulating microglial activities during neurodegenerative disease progression. In this review, we discussed the cellular interactions and the physiological roles of neural cells with other cell types including endothelial cells and microglia based on iPSC models. The therapeutic roles of MSCsmore »in treating neural degeneration and pathological roles of microglia in neurodegenerative disease progression were also discussed.« less
2. Dynamic Load Model Systems of Tendon Inflammation and Mechanobiology

   https://doi.org/10.3389/fbioe.2022.896336  

   Benage, Lindsay G. ; Sweeney, James D. ; Giers, Morgan B. ; Balasubramanian, Ravi ( July 2022 , Frontiers in Bioengineering and Biotechnology)

   Dynamic loading is a shared feature of tendon tissue homeostasis and pathology. Tendon cells have the inherent ability to sense mechanical loads that initiate molecular-level mechanotransduction pathways. While mature tendons require physiological mechanical loading in order to maintain and fine tune their extracellular matrix architecture, pathological loading initiates an inflammatory-mediated tissue repair pathway that may ultimately result in extracellular matrix dysregulation and tendon degeneration. The exact loading and inflammatory mechanisms involved in tendon healing and pathology is unclear although a precise understanding is imperative to improving therapeutic outcomes of tendon pathologies. Thus, various model systems have been designed to help elucidate the underlying mechanisms of tendon mechanobiology via mimicry of the in vivo tendon architecture and biomechanics. Recent development of model systems has focused on identifying mechanoresponses to various mechanical loading platforms. Less effort has been placed on identifying inflammatory pathways involved in tendon pathology etiology, though inflammation has been implicated in the onset of such chronic injuries. The focus of this work is to highlight the latest discoveries in tendon mechanobiology platforms and specifically identify the gaps for future work. An interdisciplinary approach is necessary to reveal the complex molecular interplay that leads to tendon pathologies and will ultimatelymore »identify potential regenerative therapeutic targets.« less
3. Controlled Aggregation Enhances Immunomodulatory Potential of Mesenchymal Stromal Cell Aggregates

   https://doi.org/10.1002/sctm.19-0414  

   Xie, Angela W. ; Zacharias, Nicholas A. ; Binder, Bernard Y. K. ; Murphy, William L. ( April 2021 , Stem Cells Translational Medicine)

   Human mesenchymal stromal cells (MSCs) are promising candidates for cell therapy due to their ease of isolation and expansion and their ability to secrete antiapoptotic, pro-angiogenic, and immunomodulatory factors. Three-dimensional (3D) aggregation “self-activates” MSCs to augment their pro-angiogenic and immunomodulatory potential, but the microenvironmental features and culture parameters that promote optimal MSC immunomodulatory function in 3D aggregates are poorly understood. Here, we generated MSC aggregates via three distinct methods and compared them with regard to their (a) aggregate structure and (b) immunomodulatory phenotype under resting conditions and in response to inflammatory stimulus. Methods associated with fast aggregation kinetics formed aggregates with higher cell packing density and reduced extracellular matrix (ECM) synthesis compared to those with slow aggregation kinetics. While all three methods of 3D aggregation enhanced MSC expression of immunomodulatory factors compared to two-dimensional culture, different aggregation methods modulated cells' temporal expression of these factors. A Design of Experiments approach, in which aggregate size and aggregation kinetics were systematically covaried, identified a significant effect of both parameters on MSCs' ability to regulate immune cells. Compared to small aggregates formed with fast kinetics, large aggregates with slow assembly kinetics were more effective at T-cell suppression and macrophage polarization toward anti-inflammatorymore »phenotypes. Thus, culture parameters including aggregation method, kinetics, and aggregate size influence both the structural properties of aggregates and their paracrine immunomodulatory function. These findings underscore the utility of engineering strategies to control properties of 3D MSC aggregates, which may identify new avenues for optimizing the immunomodulatory function of MSC-based cell therapies.

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4. The SMAC mimetic LCL-161 selectively targets JAK2V617F mutant cells

   https://doi.org/10.1186/s40164-019-0157-6  

   Craver, Brianna M. ; Nguyen, Thanh Kim ; Nguyen, Jenny ; Nguyen, Hellen ; Huynh, Christy ; Morse, Sarah J. ; Fleischman, Angela G. ( December 2020 , Experimental Hematology & Oncology)

   Abstract Background Evasion from programmed cell death is a hallmark of cancer and can be achieved in cancer cells by overexpression of inhibitor of apoptosis proteins (IAPs). Second mitochondria-derived activator of caspases (SMAC) directly bind to IAPs and promote apoptosis; thus, SMAC mimetics have been investigated in a variety of cancer types. particularly in diseases with high inflammation and NFĸB activation. Given that elevated TNFα levels and NFĸB activation is a characteristic feature of myeloproliferative neoplasms (MPN), we investigated the effect of the SMAC mimetic LCL-161 on MPN cell survival in vitro and disease development in vivo. Methods To investigate the effect of the SMAC mimetic LCL-161 in vitro, we utilized murine and human cell lines to perform cell viability assays as well as primary bone marrow from mice or humans with JAK2 V617F –driven MPN to interrogate myeloid colony formation. To elucidate the effect of the SMAC mimetic LCL-161 in vivo, we treated a JAK2 V617F –driven mouse model of MPN with LCL-161 then assessed blood counts, splenomegaly, and myelofibrosis. Results We found that JAK2 V617F -mutated cells are hypersensitive to the SMAC mimetic LCL-161 in the absence of exogenous TNFα. JAK2 kinase activity and NFĸB activation is requiredmore »for JAK2 V617F -mediated sensitivity to LCL-161, as JAK or NFĸB inhibitors diminished the differential sensitivity of JAK2 V617F mutant cells to IAP inhibition. Finally, LCL-161 reduces splenomegaly and may reduce fibrosis in a mouse model of JAK2 V617F -driven MPN. Conclusion LCL-161 may be therapeutically useful in MPN, in particular when exogenous TNFα signaling is blocked. NFĸB activation is a characteristic feature of JAK2 V617F mutant cells and this sensitizes them to SMAC mimetic induced killing even in the absence of TNFα. However, when exogenous TNFα is added, NFĸB is activated in both mutant and wild-type cells, abolishing the differential sensitivity. Moreover, JAK kinase activity is required for the differential sensitivity of JAK2 V617F mutant cells, suggesting that the addition of JAK2 inhibitors to SMAC mimetics would detract from the ability of SMAC mimetics to selectively target JAK2 V617F mutant cells. Instead, combination therapy with other agents that reduce inflammatory cytokines but preserve JAK2 signaling in mutant cells may be a more beneficial combination therapy in MPN.« less
5. Dysregulation of TLR9 in neonates leads to fatal inflammatory disease driven by IFN-γ

   https://doi.org/10.1073/pnas.1911579117  

   Stanbery, Alison G. ; Newman, Zachary R. ; Barton, Gregory M. ( January 2020 , Proceedings of the National Academy of Sciences)

   Recognition of self-nucleic acids by innate immune receptors can lead to the development of autoimmune and/or autoinflammatory diseases. Elucidating mechanisms associated with dysregulated activation of specific receptors may identify new disease correlates and enable more effective therapies. Here we describe an aggressive in vivo model of Toll-like receptor (TLR) 9 dysregulation, based on bypassing the compartmentalized activation of TLR9 in endosomes, and use it to uncover unique aspects of TLR9-driven disease. By inducing TLR9 dysregulation at different stages of life, we show that while dysregulation in adult mice causes a mild systemic autoinflammatory disease, dysregulation of TLR9 early in life drives a severe inflammatory disease resulting in neonatal fatality. The neonatal disease includes some hallmarks of macrophage activation syndrome but is much more severe than previously described models. Unlike TLR7-mediated disease, which requires type I interferon (IFN) receptor signaling, TLR9-driven fatality is dependent on IFN-γ receptor signaling. NK cells are likely key sources of IFN-γ in this model. We identify populations of macrophages and Ly6C^himonocytes in neonates that express high levels of TLR9 and low levels of TLR7, which may explain why TLR9 dysregulation is particularly consequential early in life, while symptoms of TLR7 dysregulation take longer to manifest. Overall,more »this study demonstrates that inappropriate TLR9 responses can drive a severe autoinflammatory disease under homeostatic conditions and highlights differences in the diseases resulting from inappropriate activation of TLR9 and TLR7.

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