LMP student seminars: 10 December

Each week during term time, MSc and PhD candidates in the Department of Laboratory Medicine and Pathobiology present their research.

Anyone is welcome. No need to register.

Location: Medical Sciences Building, rooms 4171 or 4279, see below.

As part of the core research curriculum, students taking LMP1001/2/3: Graduate Seminars in Laboratory Medicine and Pathobiology will present their projects. Please see abstracts below.

Group 2: Cancer, Development and Aging

Location: MSB 4171

Mingyuan Wan

• Title: Examining the role of atrophic tubule as an initial stage in the development of papillary renal cell neoplasms understanding the disease pathogenesis
• Supervisor: Dr. Rola Saleeb

Group 1: Brain and Neuroscience

Location: MSB 4279

Alissa Pak

• Title: Unveiling the role of Pten in Müller glial development and regeneration
• Supervisor: Dr. Carol Schuurmans

Abstracts

Mingyuan Wan: Examining the role of atrophic tubule as an initial stage in the development of papillary renal cell neoplasms understanding the disease pathogenesis

Introduction: Patients with end-stage renal disease (ESRD) are at an increased risk of developing papillary renal cell carcinoma (PRCC). Papillary adenoma (PA), widely recognized as the precursor to PRCC, is also frequently found in the ESRD. Atrophic tubules (AP) are a hall mark for end-stage kidney (EK). Recent studies showed a progenitor cell population increased expression in AP and shared molecular characteristics with PRCC cells, pointing to its potential role as tumor origin. However, this observation is not seen in other RCC lesions such as multilocular cystic renal neoplasm of low malignant potential (MCNLMP) or chromophobe RCC (chRCC). This study aims to explore the role of EK in the development of PA, the precursor lesion to PRCC.

Methods: GeoMx digital spatial profiling with whole transcriptomic assay was performed on three tissue slides, containing normal, EK (AP area), PA, MCNLMP, and chRCC. MCNLMP and chRCC served as negative controls. Differential gene expression analysis (DESeq2), pathway enrichment analysis (GSEA), and consensus clustering were performed on the GeoMx data.

Results: Clustering analysis showed that EK clustered with PA, but not with chRCC or MCNLMP. Pathway enrichment analysis indicate EK shared 94% of oncogenic and 92% of developmental pathways with PA, but no oncogenic pathways and only 16% of developmental pathways with chRCC, and none with MCNLMP. Specifically, kidney developmental and regenerative pathways, including WNT, NOTCH, and TGF-beta, were enriched in both EK and PA. Both EK and PA exhibited increased expression of renal progenitor cell markers (CD133, CD24, CD106, SOX9, PAX8), as well as other progenitor related markers (VIM, KRT7, KRT19, and BCL2).

Conclusion: The increased expression of progenitor markers and kidney developmental pathways suggests a rise of progenitor cell population in EK. Thus, we propose using the term “proliferating tubules” instead of “atrophic tubules” to more accurately reflect the active biological state of the tubules in EK. The high overlap of progenitor markers and pathway profiles between EK and PA supports the idea that progenitor cells in EK may be the origin to PA, aligning with prior findings linking them to PRCC. Further exploration would extend the understanding of the pathogenesis from these progenitor cells to PA and later on PRCC, allowing the discovery of biomarkers for early detection of PRCC. This is of particular benefit for those with increased risk as the ESRD patients.

Alissa Pak: Unveiling the role of Pten in Müller glial development and regeneration

Müller glia are the principal glial cells in the retina, playing a critical role in maintaining retinal homeostasis. In response to injury, Müller glia undergo reactive gliosis; however, unlike in zebrafish, mammalian Müller glia lack the intrinsic capacity to regenerate retinal neurons. Loss of the tumor suppressor gene Pten activates the PI3K/AKT/mTOR signalling pathway, which has been implicated in stem cell activation across various lineages. To investigate the role of Pten in Müller glia development and activation, we generated a conditional knock-out (cKO) mouse model using a retinal progenitor cell (RPC)-specific Cre driver, targeting all derivative retinal neurons and Müller glia. In Pten-cKO retinas, Müller glial nuclei aberrantly delaminate into the outer nuclear layer, where photoreceptors reside, resembling interkinetic nuclear movements seen in regenerative fish retinas. Transcriptomic profiling of enriched Müller glia revealed that Pten-cKO cells express mature Müller glia markers (Glul, Slc1a3, Rlbp1). However, differentiation inhibitors (Id1, Id2) were significantly downregulated, likely signifying a shift away from glial quiescence and towards a primed or reprogramming-competent state. Gliosis-associated genes, including Gfap, Padi2, and Slc1a2, were upregulated in Pten-cKO Müller glia, a sign of a stress response. Finally, following MNU-induced retinal injury, Pten-deficient retinas exhibited a reduction in SOX9+ Müller glia, implying cellular loss or altered identity through SOX9 downregulation. Collectively, our data establish Pten as a key regulator of Müller glial reactive behaviour, and potentially regenerative capacity. These findings position Pten as a compelling therapeutic target for promoting neuroregeneration and treating retinal degenerative conditions. 

Contact

No need to register.

Contact lmp.grad@utoronto.ca with any questions.