Biology subjects

Dattoli, A. A.

Publications and source records attributed to Dattoli, A. A..

3 recordsLinked to original sources

bioRxiv2026

Generation of hypoimmunogenic gastric insulin-secreting organoids

Gastric insulin-secreting organoids (GINS) represent a promising source of {beta}-like cells for type 1 diabetes (T1D) therapy. In same-donor comparisons with induced pluripotent stem cell-derived islets (iPSC-islets), GINS displayed robust glucose responsiveness and reduced expression of key T1D autoantigens. Importantly, GINS exhibited decreased susceptibility to cytotoxicity mediated by engineered HLA-matched preproinsulin-specific effector T cells (Avatar Teffs) and a distinct transcriptional profile enriched for immune-modulatory and stress-adaptive gene programs. To enhance immune evasion, we engineered gastric stem cells to overexpress Programmed Death Ligand 1 (PD-L1) in an inducible manner. PD-L1+ GINS maintained normal functionality, while exhibiting improved survival under allogeneic Avatar Teff challenge in a MHC class I-independent fashion. We evaluated PD-L1-mediated protection against autologous Avatar Teff attack using an endothelialized microfluidic platform recapitulating physiologic immune interactions. T cells show reduced infiltration into PD-L1 GINS, resulting in significantly higher organoid viability compared to control GINS. Together, these findings identify GINS as a functional and engineerable {beta}-like cell platform with intrinsic hypoimmunogenic features, and support PD-L1 engineering as a strategy to enhance immune protection for both allogeneic and autologous transplantation in T1D.

immunology↗

bioRxiv2020

CENP-C regulates centromere assembly, asymmetry and epigenetic age in Drosophila germline stem cells.

Germline stem cells divide asymmetrically to produce one new daughter stem cell and one daughter cell that will subsequently undergo meiosis and differentiate to generate the mature gamete. The silent sister hypothesis proposes that in asymmetric divisions, the selective inheritance of sister chromatids carrying specific epigenetic marks between stem and daughter cells impacts cell fate. To facilitate this selective inheritance, the hypothesis specifically proposes that the centromeric region of each sister chromatid is distinct. In Drosophila germ line stem cells (GSCs), it has recently been shown that the centromeric histone CENP-A (called CID in flies) - the epigenetic determinant of centromere identity - is asymmetrically distributed between sister chromatids. In these cells, CID deposition occurs in G2 phase such that sister chromatids destined to end up in the stem cell harbour more CENP-A, assemble more kinetochore proteins and capture more spindle microtubules. These results suggest a potential mechanism of mitotic drive that might bias chromosome segregation. Here we report that the inner kinetochore protein CENP-C, is required for the assembly of CID in G2 phase in GSCs. Moreover, CENP-C is required to maintain a normal asymmetric distribution of CID between stem and daughter cells. In addition, we find that CID is lost from centromeres in aged GSCs and that a reduction in CENP-C accelerates this loss. Finally, we show that CENP-C depletion in GSCs disrupts the balance of stem and daughter cells in the ovary, shifting GSCs toward a self-renewal tendency. Ultimately, we provide evidence that centromere assembly and maintenance via CENP-C is required to sustain asymmetric divisions in female Drosophila GSCs.

cell biology↗

bioRxiv2019

CENP-A drives asymmetric cell division and maintains stem identity

Centromeres, chromosomal loci essential for genome integrity, are epigenetically defined by CENP-A-containing chromatin. Recent studies suggest that parental CENP-A is asymmetrically distributed upon stem cell asymmetric division. However, a direct link between centromeres and stem cell identity has not been demonstrated. We show that Drosophila female germline stem cells (GSCs) and neuroblasts assemble centromeres between G2-phase and prophase, requiring CYCLIN A. Intriguingly, chromosomes that will be inherited by GSCs incorporate more CENP-A and capture more spindle fibers at pro-metaphase. Furthermore, over-expression of CAL1 (Drosophila CENP-A assembly factor) causes GSC-like tumours, while over-expression of both CENP-A and CAL1 promotes stem cell self-renewal. Finally, once centromeres have been assembled in GSCs, continued CENP-A assembly is not required in differentiating cells outside of the niche and CAL1 becomes dispensable. According to our results CENP-A regulates stem cell identity/maintenance. Moreover, crucial centromere assembly occurs in the niche prior to oocyte meiosis.

cell biology↗