Biology subjects

McMahon, A. P.

Publications and source records attributed to McMahon, A. P..

3 recordsLinked to original sources

bioRxiv2018

Transcriptional trajectories of human kidney disease progression

Our molecular understanding of clinical conditions progressing from acute organ injury to irreversible dysfunction is limited. We used renal transplantation as a model to characterize the transcriptional response along the transition from acute kidney injury to allograft fibrosis in humans. The integrated analysis of 163 transcriptomes with machine learning techniques identified shared and divergent transcriptional trajectories determining distinct clinical outcomes in a heterogeneous population. The molecular map of renal responses to injury was validated in a mouse ischemia-reperfusion injury model and highlighted early markers of disease progression. This generally applicable approach opens the way for an unbiased analysis of progressive diseases.

pathology↗

bioRxiv2018

Late B lymphocyte action in dysfunctional tissue repair following kidney injury and transplantation

The mechanisms initiating the late immune response to allografts are poorly understood. Through transcriptome analysis of serial protocol biopsies in kidney transplant recipients, we found a tight correlation between the initial response to kidney injury and a late B lymphocyte signature associated with renal dysfunction and fibrosis, suggesting a link between dysfunctional repair and immunoreactivity. To specifically investigate the immunological consequences of dysfunctional repair, we followed the mouse kidney up to 18 months after ischemia/reperfusion. Even in the absence of foreign antigens we identified a sustained immune response in conjunction with the transition to chronic kidney damage. This tissue-driven immunological process involved both the innate and the adaptive immune system and eventually induced an antigen-driven proliferation, selection and maturation of B lymphocytes into broadly-reacting antibody secreting cells. These findings reveal an unappreciated role of dysfunctional tissue repair on local immunoregulation with a particular relevance for late transplantation immunobiology.

immunology↗

bioRxiv2017

A simple bioreactor-based method to generate kidney organoids from pluripotent stem cells

Kidney organoids generated from human pluripotent stem cells have the potential to revolutionize how kidney development and injury are studied. Current protocols are technically complex and suffer from poor reproducibility and high reagent costs restricting scalability. To overcome these issues, we have established a simple, inexpensive and robust method to grow kidney organoids in bulk from human induced pluripotent stem cells. Our organoids develop tubular structures by day (d) 8 and show optimal tissue morphology at d14. A comparison with fetal human kidney suggests that d14 organoid renal structures most closely resemble capillary loop stage nephrons. We show that deletion of HNF1B, a transcription factor linked to congenital kidney defects, interferes with tubulogenesis, validating our experimental system for studying renal developmental biology. Taken together, our protocol provides a fast, efficient and cost-effective method for generating large quantities of human fetal kidney tissue, enabling the study of normal and aberrant human renal development.

developmental biology↗