UM171 Preserves Epigenetic Marks that Are Reduced in Ex Vivo Culture of Human HSCs via Potentiation of the CLR3-KBTBD4 Complex

Chagraoui, Jalila; Girard, Simon; Spinella, Jean-François; Simon, Laura; Bonneil, Éric; Mayotte, Nadine; MacRae, Tara; Coulombe-Huntington, Jasmin; Bertomeu, Thierry; Moison, Céline; Tomellini, Elisa; Thibault, Pierre; Tyers, Mike; Marinier, Anne; Sauvageau, Guy

doi:10.1016/j.stem.2020.12.002

Cited by 57 publications

(46 citation statements)

References 50 publications

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“…This is not surprising for two reasons. First, UM171a was suggested to share a common molecular pathway with tranylcypromine and potentially other LSD1 inhibitors, which can regulate the expression of both stem cell as well as classical and non-classical MHCI-related genes [ 34 , 35 ]. This may explain the functional discrepancy observed between MEF and MSC responses.…”

Section: Discussionmentioning

confidence: 99%

UM171A-induced ROS promote antigen cross-presentation of immunogenic peptides by bone marrow-derived mesenchymal stromal cells

et al. 2022

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Background Mesenchymal stromal cells (MSCs) have been extensively used in the clinic due to their exquisite tissue repair capacity. However, they also hold promise in the field of cellular vaccination as they can behave as conditional antigen presenting cells in response to interferon (IFN)-gamma treatment under a specific treatment regimen. This suggests that the immune function of MSCs can be pharmacologically modulated. Given the capacity of the agonist pyrimido-indole derivative UM171a to trigger the expression of various antigen presentation-related genes in human hematopoietic progenitor cells, we explored the potential use of UM171a as a means to pharmacologically instill and/or promote antigen presentation by MSCs. Methods Besides completing a series of flow-cytometry-based phenotypic analyses, several functional antigen presentation assays were conducted using the SIINFEKL-specific T-cell clone B3Z. Anti-oxidants and electron transport chain inhibitors were also used to decipher UM171a’s mode of action in MSCs. Finally, the potency of UM171a-treated MSCs was evaluated in the context of therapeutic vaccination using immunocompetent C57BL/6 mice with pre-established syngeneic EG.7T-cell lymphoma. Results Treatment of MSCs with UM171a triggered potent increase in H2-Kb cell surface levels along with the acquisition of antigen cross-presentation abilities. Mechanistically, such effects occurred in response to UM171a-mediated production of mitochondrial-derived reactive oxygen species as their neutralization using anti-oxidants or Antimycin-A mitigated MSCs’ ability to cross-present antigens. Processing and presentation of the immunogenic ovalbumin-derived SIINFEKL peptide was caused by de novo expression of the Psmb8 gene in response to UM171a-triggered oxidative stress. When evaluated for their anti-tumoral properties in the context of therapeutic vaccination, UM171a-treated MSC administration to immunocompetent mice with pre-established T-cell lymphoma controlled tumor growth resulting in 40% survival without the need of additional supportive therapy and/or standard-of-care. Conclusions Altogether, our findings reveal a new immune-related function for UM171a and clearly allude to a direct link between UM171a-mediated ROS induction and antigen cross-presentation by MSCs. The fact that UM171a treatment modulates MSCs to become antigen-presenting cells without the use of IFN-gamma opens-up a new line of investigation to search for additional agents capable of converting immune-suppressive MSCs to a cellular tool easily adaptable to vaccination. Graphical abstract

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Section: Discussionmentioning

confidence: 99%

UM171A-induced ROS promote antigen cross-presentation of immunogenic peptides by bone marrow-derived mesenchymal stromal cells

et al. 2022

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“…Cellular reaction to manipulation, whether it be ex vivo culture, electroporation, viral transduction, or exposure to foreign DNA, RNA, or protein, with varied stress responses, such as DNAdamage, inflammatory/antiviral, and senescence responses, may modify genomic repair, cell cycle progression, susceptibility to cell death, and engraftment potential. [117][118][119] Genetic modifiers and nongenetic factors such as epigenetic status and cell cycle stage may contribute to genome editing outcomes. [120][121][122] For ex vivo gene-modified products, genetic modification may be incomplete at the time of cell infusion.…”

Section: Potential Sources Of Variation In Engraftment Outcomesmentioning

confidence: 99%

Editing outside the body: Ex vivo gene-modification for β-hemoglobinopathy cellular therapy

Rosanwo

Bauer

2021

Molecular Therapy

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“…Our results demonstrate that the addition of UM171 and SR-1 to SGF (TPO, IL-6, SCF and FLT-3) supported selfrenewal of CD34 + -derived cells over a two-week expansion culture when compared to SGF or either UM171 or SR-1 added individually, which was most likely due to the fact that both molecules target different pathways (Boitano et al 2010;Chagraoui et al 2021). Previous expansion studies using TPO, FLT-3, IL-6, IL-3 and SCF (Petzer et al 1996) resulted in poor expansion and differentiation of CD34 + cells.…”

Section: Discussionmentioning

confidence: 79%

Effect of expansion of human umbilical cord blood CD34 + cells on neurotrophic and angiogenic factor expression and function

et al. 2022

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The use of CD34 + cell-based therapies has largely been focused on haematological conditions. However, there is increasing evidence that umbilical cord blood (UCB) CD34 + -derived cells have neuroregenerative properties. Due to low cell numbers of CD34 + cells present in UCB, expansion is required to produce sufficient cells for therapeutic purposes, especially in adults or when frequent applications are required. However, it is not known whether expansion of CD34 + cells has an impact on their function and neuroregenerative capacity. We addressed this knowledge gap in this study, via expansion of UCB-derived CD34 + cells using combinations of LDL, UM171 and SR-1 to yield large numbers of cells and then tested their functionality. CD34 + cells expanded for 14 days in media containing UM171 and SR-1 resulted in over 1000-fold expansion. The expanded cells showed an up-regulation of the neurotrophic factor genes BDNF, GDNF, NTF-3 and NTF-4, as well as the angiogenic factors VEGF and ANG. In vitro functionality testing showed that these expanded cells promoted angiogenesis and, in brain glial cells, promoted cell proliferation and reduced production of reactive oxygen species (ROS) during oxidative stress. Collectively, this study showed that our 14-day expansion protocol provided a robust expansion that could produce enough cells for therapeutic purposes. These expanded cells, when tested in in vitro, maintained functionality as demonstrated through promotion of cell proliferation, attenuation of ROS production caused by oxidative stress and promotion of angiogenesis.

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UM171 Preserves Epigenetic Marks that Are Reduced in Ex Vivo Culture of Human HSCs via Potentiation of the CLR3-KBTBD4 Complex

Cited by 57 publications

References 50 publications

UM171A-induced ROS promote antigen cross-presentation of immunogenic peptides by bone marrow-derived mesenchymal stromal cells

UM171A-induced ROS promote antigen cross-presentation of immunogenic peptides by bone marrow-derived mesenchymal stromal cells

Editing outside the body: Ex vivo gene-modification for β-hemoglobinopathy cellular therapy

Effect of expansion of human umbilical cord blood CD34 + cells on neurotrophic and angiogenic factor expression and function

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