About

Ali Naji, M.D., Ph.D., is the Jonathan E. Rhoads Professor of Surgical Science II at the University of Pennsylvania Perelman School of Medicine. He serves as an Attending Staff member at the Hospital of the University of Pennsylvania and is the Associate Director of the Institute for Diabetes, Obesity, and Metabolism at the same institution. His educational background includes diplomas from Shiraz University School of Arts and Sciences and Shiraz University School of Medicine in Iran, followed by an M.D. from Shiraz University and a Ph.D. in Immunology from the University of Pennsylvania School of Medicine. His research expertise focuses on mechanisms regulating the maintenance and loss of immune tolerance to tissue-specific antigens in autoimmune diseases and transplantation. His work involves studying the immune pathogenesis of autoimmune diabetes, particularly using the non-obese diabetic (NOD) mouse model to understand T cell-mediated destruction of insulin-producing beta cells. His laboratory investigates cellular antigen presentation processes, the role of B lymphocytes, and the mechanisms of T cell tolerance and activation in autoimmune and transplant settings. His research aims to elucidate the parameters dictating immune tolerance and activation, with the goal of designing therapeutic strategies to modulate auto- and allo-reactive T cell responses.

Research topics

• Medicine
• Biology
• Endocrinology
• Surgery
• Internal medicine
• Genetics
• Computer Science
• Virology
• Molecular biology
• Cell biology
• Bioinformatics
• Psychiatry
• Biomedical engineering
• Intensive care medicine
• Psychology
• Immunology
• Pharmacology

Selected publications

• Mathematical Treatment of Management Triangle to be Used Numerically as a Tool in Performance Measuring of Construction Projects

  Al-Mustaqbal Journal of Sustainability in Engineering Sciences · 2025-01-13

  articleOpen access

  This study introduces a mathematical treatment to the triangle of management to be used numerically as a tool in measuring the performance of projects in view of the adopted priorities during executing phases of the projects. The actual outputs of construction projects are usually deviated from planned targets by more or less. If a group of projects within a unique attitude are considered , a trend can be investigated representing the biased efforts to one of the three targets : delivering the project on time , in the planned cost and in the specified quality. This study showed that the triangle of management can be used to represent graphically the performance of the construction projects. From this representation the managerial priorities can be obtained. The deviations from the ideal case can be obtained also . An application is made on fifty construction projects executed in Iraq . Results showed that quality is the first priority followed by time and the last priority is the cost requirement . The mean value of the deviation in all construction projects is 18.5 which is reflecting the unbalancing in priorities.

  PublisherDOI

• Detection of HTLV-1 and -2 infections in relation to the immune factor soluble HLA-G in adult Iraqi lymphoma patients

  Regulatory Mechanisms in Biosystems · 2025-10-31

  articleOpen accessSenior author

  The o bjective of this article is to determin e the expression of sHLA-G antigen in HTLV-1 and HTLV-2 l ymphoma cases and t o confirm positive infection cases of HTLV-1 and distinguish ra ndom c ases from negative by using the r eal-time polym e rase chain reaction (RT-PCR) technique. This cross-sectional study involved 180 lymphoma patients recruited from the Blood and Bone Marrow Transplantation Center at the Teaching Hospital, Medical City, Baghdad, National Center for Blood Diseases, A l -Mustansiriya University, and A l -Imamain A l -Kadhimain Medical City. A m inority of the participant s were ELISA positive to HTLV-1 . T he same is true for the TaqMan probe RT-PCR result, the mean levels of HLA-G did n o t differ significantly between lymphoma participants who were HTLV-1 positive and those who were HTLV-1 negative. All lymphoma participants in this study were HTLV-2 negative . In this study, lymphoma patients were less predominantly affected by HTLV-1 and HTLV-2 infection. Therefore, it is important to implement screening protocols to control the transmission and complication of this virus in lymphoma patient s . Further research will be necessary , involving all provinces of Iraq , to reveal the exact number of virus infe c tion s .

  PublisherOA PDFDOI

• ChemPerturb-seq screen identifies a small molecule cocktail enhancing human beta cell survival after subcutaneous transplantation

  Cell stem cell · 2025-06-24 · 5 citations

  article
  PublisherDOI

• Clinicopathological Significance of Immunohistochemical Expression of SOX2 Protein in Urothelial Carcinoma of Urinary Bladder in a Sample of Iraqi Patients

  Iraqi postgraduate medical journal · 2025-10-01

  articleOpen accessSenior author

  Background:Bladder carcinoma is the tenth most common carcinoma worldwide. It is one of the most common ten malignancies in Iraq. Sex determining region Y-box 2 (SOX2) is a transcription factor. It plays an essential role in cell fate determination. Aberrant expression of SOX2 has been reported in many types of carcinomas SOX2 expression is said to be associated with tumor progression.Objective:To evaluate the prognostic impact of SOX2 immunohistochemical expression in the urothelial carcinoma of the urinary bladder.Materials and methods:This is a retrospective study of fifty patients with urothelial carcinoma of bladder carried out in the Babylon Training Center for Histopathology during the period from December 2022 through December 2023. Two sections from each paraffin embedded tissue block were taken, one for hematoxylin and eosin staining for histopathology revision and the other for immunohistochemistry staining of SOX2.Results:In this study, 78.0% (n=39) showed low SOX2 expression, and 22.0% (n=26) showed ‘high’ SOX2 expression. A significant association was found between SOX2 expression and tumor stage and muscle invasion status.Conclusions:In the current study, we concluded that there was a significant association between SOX2 expression and poor prognostic factors and that SOX2 expression may help detect urothelial carcinoma patients with poor prognostic features.

  PublisherOA PDFDOI

• Circulating Tissue Specific Extracellular Vesicles for Noninvasive Monitoring of Acute Cellular Rejection in Clinical Heart Transplantation

  Transplantation · 2025-04-16 · 6 citations

  article

  BACKGROUND: There remains a critical need for biomarkers of acute cellular rejection (ACR) in heart transplantation. We hypothesized that immunopathophysiology of ACR is reflected via dynamic changes in the protein and RNA cargoes of small extracellular vesicles (sEVs) released by cardiac allograft and T cells into circulation, thus enabling noninvasive window into ACR. METHODS: T-cell sEVs were enriched using anti-CD3 antibody beads, and antidonor HLA I antibody beads for donor sEVs. Cargoes of donor sEVs (cardiac troponin T [cTnT] protein and mRNA) and T-cell sEVs (CD4, CD8, T-cell receptor proteins, miRNAs [miRs] let 7i, 101b, 21a) were compared with time-matched endomyocardial biopsy samples (n = 70) in 12 patients to postoperative day 120. RESULTS: Six patients had 11 moderate ACR (15.7%) episodes, 1 had antibody-mediated rejection, and 5 had ≤ mild ACR. By Wilcoxon rank-sum tests, cTnT protein ( P = 6.04 × 10 -5 ) and mRNA ( P = 6.87 × 10 -7 ) were decreased with moderate ACR compared with grades 0/1 ACR. T-cell sEV CD4, CD8, and TCR protein cargoes ( P ≤ 3.92 × 10 -5 ) and miRs let 7i, 101b, and 21a ( P ≤ 9.05 × 10 -5 ) were increased with moderate ACR. Successful treatment of moderate ACR led to dynamic reversal in sEV profiles, especially donor heart sEV cTnT mRNA (Spearman coefficient 0.87) and miR 21a (coefficient 0.85). CONCLUSIONS: Our first investigation in heart transplant patients demonstrated that circulating T cell-sEV and donor heart-sEV profiles enable diagnosis of moderate ACR with high diagnostic accuracy. A large sample cohort external validation study is warranted to better understand diagnostic potential of this platform for ACR monitoring in heart transplantation.

  PublisherDOI

• SEL1L-HRD1 ER-Associated Degradation Facilitates Prohormone Convertase 2 Maturation and Glucagon Production in Islet α Cells

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-20

  preprintOpen access

  Proteolytic cleavage of proglucagon by prohormone convertase 2 (PC2) is required for islet α cells to generate glucagon. However, the regulatory mechanisms underlying this process remain largely unclear. Here, we report that SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation (ERAD), a highly conserved protein quality control system responsible for clearing misfolded proteins from the ER, plays a key role in glucagon production by regulating turnover of the nascent proform of the PC2 enzyme (proPC2). Using a mouse model with SEL1L deletion in proglucagon-expressing cells, we observed a progressive decline in stimulated glucagon secretion and a reduction in pancreatic glucagon content. Mechanistically, we found that endogenous proPC2 is a substrate of SEL1L-HRD1 ERAD, and that degradation of misfolded proPC2 ensures the maturation of activation-competent proPC2 protein. These findings identify ERAD as a novel regulator of PC2 biology and an essential mechanism for maintaining α cell function.

  PublisherOA PDFDOI

• Single-cell multiome analysis supports α-to-β transdifferentiation in human pancreas

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-19 · 2 citations

  preprintOpen access

  Abstract Spontaneous transdifferentiation of pancreatic glucagon-producing alpha to insulin-secreting beta-cells has been observed in mouse but not in human islets 1 . Here, we analyzed the largest single-cell dataset of human islets to date, composed of 650,000 cells across 121 deceased organ donors, in search of transitional cell states. By integrating single-cell RNA-seq, single-nucleus ATAC-seq and single-nucleus multiome (joint RNA and ATAC profiling) datasets generated by the Human Pancreas Analysis Program (HPAP) 2,3 we identified two previously undescribed cell populations (c11 and c13 cells), which together represent transitional states between alpha- and beta-cells. Some c11 cells are insulin-positive while others are glucagon positive, but none are double-positive. C11 cells repress alpha-cell identity genes and activate beta-cell specific genes. Moreover, the transcriptomic and epigenetic profiles of c11 and c13 cells indicate a transitioning phenotype driven by lineage-specific transcription factors. Genetic lineage tracing in primary human islet cells confirmed alpha-to-beta cell transdifferentiation. C11 and c13 cells exist in all islet samples regardless of disease statuses, with type 2 diabetic samples having significantly more transitioning cells than matched non-diabetic controls. The discovery of these transitional cell types suggests a possibility for future therapy – transdifferentiating alpha-cells to beta-cell through activation of the c11 gene program.

  PublisherOA PDFDOI

• <b>Molecular Mechanisms of Human Pancreatic Islet Dysfunction Under Overnutrition Metabolic Stress</b>

  2025-08-07

  preprintOpen access

  <p dir="ltr">Metabolic stress elicits functional changes in pancreatic islets, contributing to the pathogenesis of type 2 diabetes. However, the molecular mechanisms underlying overnutrition stress in islet cells is not well understood. In our study, we subjected human islets to overnutrition with 25 mM glucose and 0.5 mM palmitic acid (glucolipotoxicity) or a control culture condition with 5.1 mM glucose. We utilized single-cell RNA sequencing to comprehensively characterize the gene expression changes between these two conditions in a cell-type specific manner. We found that among all islet endocrine cell types, alpha cells are the most resilient to glucolipotoxicity, while beta cells are the most susceptible. We also observed a reduction in cell-cell interactions within islet endocrine cells under glucolipotoxicity, alongside alterations in gene regulatory networks linked to type 2 diabetes genetic risk. Lastly, targeted drug screening underscored the critical role of histone H3K9 methyltransferases G9a and GLP in modulating the beta cell cellular response to overnutrition.</p>

  PublisherDOI

• A Cure Within for Type 1 Diabetes: Stem Cell-derived Islet Transplantation

  Transplantation · 2025-01-20

  articleSenior author
  PublisherDOI

• Molecular Mechanisms of Human Pancreatic Islet Dysfunction Under Overnutrition Metabolic Stress

  Diabetes · 2025-08-07 · 3 citations

  articleOpen access

  Metabolic stress elicits functional changes in pancreatic islets, contributing to the pathogenesis of type 2 diabetes. However, the molecular mechanisms underlying overnutrition stress in islet cells is not well understood. In our study, we subjected human islets to overnutrition with 25 mmol/L glucose and 0.5 mmol/L palmitic acid (glucolipotoxicity) or to a control culture condition with 5.1 mmol/L glucose. We used single-cell RNA sequencing to comprehensively characterize the gene expression changes between these two conditions in a cell type-specific manner. We found that among all islet endocrine cell types, α-cells were the most resilient to glucolipotoxicity, while β-cells were the most susceptible. We also observed a reduction in cell-cell interactions within islet endocrine cells under glucolipotoxicity, alongside alterations in gene regulatory networks linked to type 2 diabetes genetic risk. Finally, targeted drug screening underscored the critical role of histone H3K9 methyltransferases G9a (EHMT2) and GLP (EHMT1) in modulating the β-cell cellular response to overnutrition. ARTICLE HIGHLIGHTS: Glucolipotoxicity disrupts insulin secretion in human islets, yet its cell type-specific impacts and the molecular mechanisms driving these effects remain poorly understood. Single-cell RNA sequencing reveals β-cells as the most sensitive to glucolipotoxicity, with pronounced shifts in the gene regulatory network linked to cellular stress and lineage-specific transcription factors, while α-cells exhibit greater resilience. Cell-cell communications among islet endocrine cells are reduced under glucolipotoxicity. H3K9 methyltransferases G9a and GLP mediate glucolipotoxicity in β-cells. Our study provides a road map of how metabolic stress causally contributes to cellular dysfunction and diabetes pathogenesis.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R37DK034878

  NIH · $1.6M · 1999

• NIH Grant R33AI065356

  NIH · $1.1M · 2007

• NIH Grant R01DK044309

  NIH · $1.4M · 2000

• Penn integrated Human Pancreas procurement and Analysis Program

  NIH · $17.8M · 2016–2021

• NIH Grant R01AM034878

  NIH · $138k · 1987

Frequent coauthors

• Clyde F. Barker

  Hospital of the University of Pennsylvania

  170 shared

• James F. Markmann

  Massachusetts General Hospital

  118 shared

• Chengyang Liu

  68 shared

• Hooman Noorchashm

  Huntsworth Health (United States)

  56 shared

• Klaus H. Kaestner

  University of Pennsylvania

  54 shared

• Peter P. Reese

  University of Pennsylvania

  51 shared

• Michael R. Rickels

  University of Pennsylvania

  47 shared

• Susan Rostami

  California University of Pennsylvania

  46 shared

Education

• Other

  Shiraz University School of Arts and Sciences

  1964

• Other

  Shiraz University School of Medicine

  1968

• M.D.

  Shiraz University

  1970

• Ph.D., Immunology

  University of Pennsylvania School of Medicine

  1981