Survival advantage of native and engineered T cells is acquired by mitochondrial transfer from mesenchymal stem cells

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dc.coverageDOI: 10.1186/s12967-024-05627-4
dc.creatorCourt, Angela C.
dc.creatorParra-Crisóstomo, Eliseo
dc.creatorCastro-Córdova, Pablo
dc.creatorAbdo, Luiza
dc.creatorAragão, Emmanuel Arthur Albuquerque
dc.creatorLorca, Rocío
dc.creatorFigueroa, Fernando E.
dc.creatorBonamino, Martín Hernán
dc.creatorKhoury, Maroun
dc.date2024
dc.date.accessioned2025-11-18T19:43:36Z
dc.date.available2025-11-18T19:43:36Z
dc.description<p>Background: Apoptosis, a form of programmed cell death, is critical for the development and homeostasis of the immune system. Chimeric antigen receptor T (CAR-T) cell therapy, approved for hematologic cancers, retains several limitations and challenges associated with ex vivo manipulation, including CAR T-cell susceptibility to apoptosis. Therefore, strategies to improve T-cell survival and persistence are required. Mesenchymal stem/stromal cells (MSCs) exhibit immunoregulatory and tissue-restoring potential. We have previously shown that the transfer of umbilical cord MSC (UC-MSC)-derived mitochondrial (MitoT) prompts the genetic reprogramming of CD3<sup>+</sup> T cells towards a T<sub>reg</sub> cell lineage. The potency of T cells plays an important role in effective immunotherapy, underscoring the need for improving their metabolic fitness. In the present work, we evaluate the effect of MitoT on apoptotis of native T lymphocytes and engineered CAR-T cells. Methods: We used a cell-free approach using artificial MitoT (Mitoception) of UC-MSC derived MT to peripheral blood mononuclear cells (PBMCs) followed by RNA-seq analysis of CD3<sup>+</sup> MitoT<sup>pos</sup> and MitoT<sup>neg</sup> sorted cells. Target cell apoptosis was induced with Staurosporine (STS), and cell viability was evaluated with Annexin V/7AAD and TUNEL assays. Changes in apoptotic regulators were assessed by flow cytometry, western blot, and qRT-PCR. The effect of MitoT on 19BBz CAR T-cell apoptosis in response to electroporation with a non-viral transposon-based vector was assessed with Annexin V/7AAD. Results: Gene expression related to apoptosis, cell death and/or responses to different stimuli was modified in CD3<sup>+</sup> T cells after Mitoception. CD3<sup>+</sup>MitoT<sup>pos</sup> cells were resistant to STS-induced apoptosis compared to MitoT<sup>neg</sup> cells, showing a decreased percentage in apoptotic T cells as well as in TUNEL<sup>+</sup> cells. Additionally, MitoT prevented the STS-induced collapse of the mitochondrial membrane potential (MMP) levels, decreased caspase-3 cleavage, increased BCL2 transcript levels and BCL-2-related BARD1 expression in FACS-sorted CD3<sup>+</sup> T cells. Furthermore, UC-MSC-derived MitoT reduced both early and late apoptosis in CAR-T cells following electroporation, and exhibited an increasing trend in cytotoxic activity levels. Conclusions: Artificial MitoT prevents STS-induced apoptosis of human CD3<sup>+</sup> T cells by interfering with the caspase pathway. Furthermore, we observed that MitoT confers protection to apoptosis induced by electroporation in MitoT<sup>pos</sup> CAR T-engineered cells, potentially improving their metabolic fitness and resistance to environmental stress. These results widen the physiological perspective of organelle-based therapies in immune conditions while offering potential avenues to enhance CAR-T treatment outcomes where their viability is compromised.</p>eng
dc.identifierhttps://investigadores.uandes.cl/en/publications/91873e41-05cf-46f8-b483-6cd7c3e9c8ce
dc.identifier.urihttps://repositorio.uandes.cl/handle/uandes/52962
dc.languageeng
dc.rightsinfo:eu-repo/semantics/openAccess
dc.sourcevol.22 (2024) nr.1 p.868
dc.subjectChimeric antigen receptor T (CAR-T) cells
dc.subjectInduced-apoptosis
dc.subjectMesenchymal stromal/stem cells
dc.subjectMitochondria transfer
dc.subjectSDG 3 - Good Health and Well-being
dc.titleSurvival advantage of native and engineered T cells is acquired by mitochondrial transfer from mesenchymal stem cellseng
dc.typeArticleeng
dc.typeArtículospa
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