Comparative analysis of iPSC-derived NK cells from two differentiation strategies reveals distinct signatures and cytotoxic activities.

Purpose: The ability to generate natural killer (NK) cells from induced pluripotent stem cells (iPSCs) has given rise to new possibilities for the large-scale production of homogeneous immunotherapeutic cellular products and opened new avenues towards the creation of "off-the-shelf" cancer immunotherapies. However, the differentiation of NK cells from iPSCs remains poorly understood, particularly regarding the ontogenic landscape of iPSC-derived NK (iNK) cells produced and the influence that the differentiation strategy employed may have on the iNK profile.

Methods: To investigate this question, we conducted a comparative analysis of two sets of iNK cells generated from the same iPSC line using two different protocols: (i) a short-term, clinically compatible feeder-free protocol corresponding to primitive hematopoiesis, and (ii) a lymphoid-based protocol representing the definitive hematopoietic step.

Direct Reprogramming of Hepatocytes Into JAK/Stat-Dependent LGR5+ Liver Cells Able to Initiate Intrahepatic Cholangiocarcinoma.

Somatic cells that have been partially reprogrammed by the factors Oct4, Sox2, Klf4, and cMyc (OSKM) have been demonstrated to be potentially tumorigenic in vitro and in vivo due to the acquisition of cancer-associated genomic alterations and the absence of OSKM clearance over time. In the present study, we obtained partially reprogrammed, SSEA1-negative cells by transducing murine hepatocytes with Δ1Δ3-deleted adenoviruses that expressed the 4 OSKM factors. We observed that, under long-term 2D and 3D culture conditions, hepatocytes could be converted into LGR5-positive cells with self-renewal capacity that was dependent on 3 cross-signaling pathways: IL6/Jak/Stat3, LGR5/R-spondin, and Wnt/β-catenin.

Impact of the overexpression of the tyrosine kinase receptor RET in the hematopoietic potential of induced pluripotent stem cells (iPSCs).

Introduction: Previous studies have suggested that the tyrosine kinase receptor RET plays a significant role in the hematopoietic potential in mice and could also be used to expand cord-blood derived hematopoietic stem cells (HSCs). The role of RET in human iPSC-derived hematopoiesis has not been tested so far.

Methods: To test the implication of RET on the hematopoietic potential of iPSCs, we activated its pathway with the lentiviral overexpression of RET or RET mutation in normal iPSCs.

Case report: Long-term voluntary Tyrosine Kinase Inhibitor (TKI) discontinuation in chronic myeloid leukemia (CML): Molecular evidence of an immune surveillance.

The classical natural history of chronic myeloid leukemia (CML) has been drastically modified by the introduction of tyrosine kinase inhibitor (TKI) therapies. TKI discontinuation is currently possible in patients in deep molecular responses, using strict recommendations of molecular follow-up due to risk of molecular relapse, especially during the first 6 months. We report here the case of a patient who voluntarily interrupted her TKI therapy.

Mesenchymal stem cells-derived secretome and extracellular vesicles: perspective and challenges in cancer therapy and clinical applications.

Stem cell-based therapies have been foreshowed as a promising therapeutic approach for the treatment of several diseases. However, in the cancer context, results obtained from clinical studies were found to be quite limited. Deeply implicated in inflammatory cues, Mesenchymal, Neural, and Embryonic Stem Cells have mainly been used in clinical trials as a vehicle to deliver and stimulate signals in tumors niche.

Patient-Derived iPSCs Reveal Evidence of Telomere Instability and DNA Repair Deficiency in Coats Plus Syndrome.

Coats plus (CP) syndrome is an inherited autosomal recessive condition that results from mutations in the conserved telomere maintenance component 1 gene (). The CTC1 protein functions as a part of the CST protein complex, a protein heterotrimer consisting of CTC1-STN1-TEN1 which promotes telomere DNA synthesis and inhibits telomerase-mediated telomere elongation. However, it is unclear how mutations may have an effect on telomere structure and function.

Evidence of Antitumor and Antimetastatic Potential of Induced Pluripotent Stem Cell-Based Vaccines in Cancer Immunotherapy.

Cancer is maintained by the activity of a rare population of self-renewing "cancer stem cells" (CSCs), which are resistant to conventional therapies. CSCs over-express several proteins shared with induced pluripotent stem cells (iPSCs). We show here that allogenic or autologous murine iPSCs, combined with a histone deacetylase inhibitor (HDACi), are able to elicit major anti-tumor responses in a highly aggressive triple-negative breast cancer, as a relevant cancer stemness model.

iPSC-Derived Organoids as Therapeutic Models in Regenerative Medicine and Oncology.

Progress made during the last decade in stem cell biology allows currently an unprecedented potential to translate these advances into the clinical applications and to shape the future of regenerative medicine. Organoid technology is amongst these major developments, derived from primary tissues or more recently, from induced pluripotent stem cells (iPSC). The use of iPSC technology offers the possibility of cancer modeling especially in hereditary cancers with germline oncogenic mutations.

iPSC-Derived Hereditary Breast Cancer Model Reveals the -Deleted Tumor Niche as a New Culprit in Disease Progression.

Tumor progression begins when cancer cells recruit tumor-associated stromal cells to produce a vascular niche, ultimately resulting in uncontrolled growth, invasion, and metastasis. It is poorly understood, though, how this process might be affected by deletions or mutations in the breast cancer type 1 susceptibility (BRCA1) gene in patients with a lifetime risk of developing breast and/or ovarian cancer. To model the BRCA1-deleted stroma, we first generated induced pluripotent stem cells (iPSCs) from patients carrying a germline deletion of exon 17 of the BRCA1 gene (BRCA1+/- who, based on their family histories, were at a high risk for cancer.

Inhibition of the RhoGTPase Cdc42 by ML141 enhances hepatocyte differentiation from human adipose-derived mesenchymal stem cells via the Wnt5a/PI3K/miR-122 pathway: impact of the age of the donor.

Background: Human adipose-derived mesenchymal stem cells (hADSCs) are promising cells that may promote hepatocyte differentiation (Hep-Dif) and improve liver function, but the involvement of Cdc42, a key small RhoGTPase which plays a crucial role in aging, is still not well established. We hypothesized that the inhibition of Cdc42 may rescue the hepatogenic potential of hADSCs derived from aged donors.

Methods: hADSCs isolated from 61 women of different ages were cultured for evaluation of the proliferation of cells, adherence, apoptosis, immunomodulation, immunophenotyping, multipotency, gene expression, and cell function during Hep-Dif.

Essential role of ATP6AP2 enrichment in caveolae/lipid raft microdomains for the induction of neuronal differentiation of stem cells.

Background: The subcellular distribution of prorenin receptor and adaptor protein ATP6AP2 may affect neurogenesis. In this study, we hypothesized that ATP6AP2 expression and subcellular relocalization from caveolae/lipid raft microdomains (CLR-Ms) to intracellular sites may correlate with neuronal differentiation (Neu-Dif) of adipose-derived mesenchymal stem cells (ADSCs).

Methods: Human ADSCs isolated from 24 healthy donors and 24 patients with neurological disorders (ND) were cultured and induced for Neu-Dif.