Biology subjects

Lawrence, M. C.

Publications and source records attributed to Lawrence, M. C..

3 recordsLinked to original sources

bioRxiv2026

Expansion and Differentiation of Adult Human Pancreas-Derived Progenitor Cells into Functional Islet-Like Organoids

Background and AimsAdult pancreas-derived islet progenitor cells (IPCs) have recently been shown to expand in culture and differentiate into endocrine-like organoids. However, translation of this approach to a clinically compatible workflow requires cell enrichment strategies and validation using tissue obtained during real-world clinical procedures. Here, we adapted our previously described IPC platform to non-endocrine pancreatic tissue fractions generated during clinical islet isolation procedures and evaluated their capacity to generate functional islet organoids. MethodsNon-endocrine pancreatic tissue fractions obtained during clinical islet isolation were expanded ex vivo and enriched using fluorescence-activated cell sorting (FACS) for CD81 and CD9, surface markers previously identified in IPC populations. Sorted cells were expanded, induced to form IPC clusters, and differentiated with ISX9 to generate islet organoids. Differentiation was assessed by gene expression analysis, flow cytometry, immunofluorescence, calcium flux assays, glucose-stimulated insulin and glucagon secretion, and single-cell RNA sequencing. ResultsClinically derived non-endocrine cell fractions yielded expandable IPC populations expressing progenitor-associated markers. FACS-purified and expanded CD81+/CD9+ IPCs were enriched with BMPR1A and P2RY1. Sorted cells generated three-dimensional BMPR1A+ and RGS16+ IPC clusters. IPC clusters differentiated into islet organoids with upregulated expression of canonical beta-and alpha-cell transcription factors. Single-cell transcriptomic profiling revealed activation of coordinated endocrine gene programs and alignment with reference human islet endocrine signatures, while the undifferentiated IPC compartment was marked by enrichment of PTX3, FST, CEMIP, and GREM1. Terminally differentiated cells exhibited depolarization-induced calcium influx and glucose-regulated insulin and glucagon secretion. ConclusionsThese findings establish an adaptable workflow for expansion and production of functional islet organoids recovered from clinically derived pancreatic tissue. This strategy may provide an unlimited autologous source of adult progenitor-derived islets for future islet cell replacement therapies in diabetes.

cell biology↗

bioRxiv2025

Identification and Characterization of Adult Islet Pancridia Cells Capable of Differentiating into Islet Organoids

Multipotent progenitor-like cells have been identified in the adult pancreas under various physiological and pathological conditions. Here, we identify and characterize a subset of adult pancreas-derived cells, termed islet pancridia cells (IPCs), that can be expanded in vitro and retain the potential for endocrine differentiation and islet cell function. Single-cell RNA sequencing of expanded pancridia revealed transcriptomic profiles resembling immature beta cells, enriched with markers of epithelial-mesenchymal transition. A CD9, PROCR subpopulation of IPCs formed IPC clusters marked by restricted expression of RGS16, a known islet progenitor marker. In vivo, co-transplantation of expanded IPCs with a subtherapeutic dose of islets significantly improved graft function and partially restored native pancreatic endocrine activity in streptozotocin-induced diabetic mice. In vitro, treatment of RGS16 IPC clusters with the small molecule ISX9 induced differentiation into islet organoids that co-expressed and secreted insulin and glucagon. ISX9-mediated differentiation was driven by calcineurin/NFAT-dependent recruitment of the histone acetyltransferase p300 and displacement of histone deacetylases (HDACs) at the RFX6 and NEUROD1 promoters. Pre-treatment with the HDAC inhibitor ITF2357 further enhanced islet cell differentiation by promoting chromatin remodeling and facilitating NFAT-targeted recruitment of p300. These findings uncover calcium-dependent and epigenetic mechanisms that regulate the differentiation of multipotent CD9, PROCR, RGS16 IPCs into functional islet organoids and offer potential strategies for regenerating islet cell mass to treat diabetes.

developmental biology↗

bioRxiv2025

Donor-Specific Digital Twin for Living Donor Liver Transplant Recovery

Liver resection initiates a meticulously coordinated hyperplasia process characterized by regulated cell proliferation that drives liver regeneration. This process concludes with the complete restoration of liver mass, showcasing the precision and robustness of this homeostasis. The remarkable capacity of the liver to regenerate rapidly into a fully functional organ has been crucial to the success of living donor liver transplantation (LDLT). In healthy livers, hepatocytes typically remain in a quiescent state (G0). However, following partial hepatectomy, these cells transition to the G1 phase to re-enter the cell cycle. Surgical resection induces various stresses, including physical injury, altered blood flow, and increased metabolic demands. These all trigger the activation and suppression of numerous genes involved in tissue repair, regeneration, and functional recovery. Both coding and noncoding RNAs detectable in the bloodstream during this process provide valuable insights into the gene responses driving liver recovery. This study integrates clinical gene expression data into a previously developed mathematical model of liver regeneration, which tracks transitions among quiescent, primed, and proliferating hepatocytes to construct virtual, patient-specific liver models. Using whole transcriptome RNA sequencing data from 12 healthy LDLT donors, collected at 14 time points over a year, we identified liver resection-specific gene expression patterns through Weighted Gene Co-expression Network Analysis (WGCNA). These patterns were organized into distinct clusters with unique transcriptional dynamics and mapped to model variables using deep learning techniques. Consequently, we developed a Personalized Progressive Mechanistic Digital Twin (PePMDT) for the livers of LDLT donors. The resulting PePMDT predicts individual patient recovery trajectories by leveraging blood-derived gene expression data to simulate regenerative responses. By transforming gene expression profiles into dynamic model variables, this approach bridges clinical data and mathematical modeling, providing a robust platform for personalized medicine. This study highlights the transformative potential of data-driven frameworks like PePMDT in advancing precision medicine and optimizing recovery outcomes for LDLT donors.

systems biology↗