Regenerating a kidney in a lymph node

Francipane, Maria Giovanna; Lagasse, Eric

doi:10.1007/s00467-015-3296-y

Cited by 6 publications

(8 citation statements)

References 61 publications

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“…Lymph nodes are a highly favorable site for ectopic cell transplantation. 19 , 29 , 30 , 31 Not only do their plasticity and highly complex vascular network provide a healthy milieu for cell engraftment and expansion, but their accessibility makes it possible to perform minimally invasive cell delivery in the clinical setting. Ultrasound-guided lymph node identification and targeting are commonly performed clinically, and multiple clinical studies have employed lymph nodes as sites for injection of immunotherapeutic agents, with patients rating the procedure comparable to a subcutaneous injection and less painful than venipuncture.…”

Section: Discussionmentioning

confidence: 99%

Ex Vivo Cell Therapy by Ectopic Hepatocyte Transplantation Treats the Porcine Tyrosinemia Model of Acute Liver Failure

Nicolas

Kaiser

Hickey³

et al. 2020

Molecular Therapy - Methods & Clinical Development

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The effectiveness of cell-based therapies to treat liver failure is often limited by the diseased liver environment. Here, we provide preclinical proof of concept for hepatocyte transplantation into lymph nodes as a cure for liver failure in a large-animal model with hereditary tyrosinemia type 1 (HT1), a metabolic liver disease caused by deficiency of fumarylacetoacetate hydrolase (FAH) enzyme. Autologous porcine hepatocytes were transduced ex vivo with a lentiviral vector carrying the pig Fah gene and transplanted into mesenteric lymph nodes. Hepatocytes showed early (6 h) and durable (8 months) engraftment in lymph nodes, with reproduction of vascular and hepatic microarchitecture. Subsequently, hepatocytes migrated to and repopulated the native diseased liver. The corrected cells generated sufficient liver mass to clinically ameliorate the acute liver failure and HT1 disease as early as 97 days post-transplantation. Integration site analysis defined the corrected hepatocytes in the liver as a subpopulation of hepatocytes from lymph nodes, indicating that the lymph nodes served as a source for healthy hepatocytes to repopulate a diseased liver. Therefore, ectopic transplantation of healthy hepatocytes cures this pig model of liver failure and presents a promising approach for the development of cures for liver disease in patients.

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Section: Discussionmentioning

confidence: 99%

Ex Vivo Cell Therapy by Ectopic Hepatocyte Transplantation Treats the Porcine Tyrosinemia Model of Acute Liver Failure

Nicolas

Kaiser

Hickey³

et al. 2020

Molecular Therapy - Methods & Clinical Development

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“…It is generally thought that improved vascularization of the organoids will aid in nephron maturation by providing better perfusion of the tissue and developmental signals, such as those coming from peritubular capillary cells and fluid flow down the nephron. Strategies to overcome these issues include the transplantation of organoids into permissible sites of immune-deficient mice where recruitment and vascularization by host blood vessels can occur (Sharmin et al, 2016, Francipane andLagasse, 2016) and the culture of organoids in microfluidic devices ('organs-on-chips'; Bhatia andIngber, 2014, Wilmer et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

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

Przepiorski

Sander

Tran

et al. 2017

Preprint

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SummaryKidney 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.

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“…Our prior studies described the LN as an attractive bioreactor supporting the engraftment and function of adult mouse hepatic, pancreatic, and thymic cells (Komori, Boone, DeWard, Hoppo, & Lagasse, ) as well as the functional maturation of several mouse embryonic tissues, including the kidney (Francipane & Lagasse, , , ).…”

Section: Overviewmentioning

confidence: 99%

“…Because the LN provided a supportive niche for the engraftment, vascularization and function of fragments from both mouse (Francipane & Lagasse, , ) and human fetal primary kidney tissues, we next asked whether it could also support functional maturation of isolated or artificially created nephron progenitors (NPs). Reciprocal interactions between the ureteric bud and the metanephric mesenchyme drive kidney development.…”

Section: Overviewmentioning

confidence: 99%

Kidney‐in‐a‐lymph node: A novel organogenesis assay to model human renal development and test nephron progenitor cell fates

Francipane

Han

Oxburgh

et al. 2019

J Tissue Eng Regen Med

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Stem cell‐derived organoids are emerging as sophisticated models for studying development and disease and as potential sources for developing organ substitutes. Unfortunately, although organoids containing renal structures have been generated from mouse and human pluripotent stem cells, there are still critical unanswered questions that are difficult to attain via in vitro systems, including whether these nonvascularized organoids have a stable and physiologically relevant phenotype or whether a suitable transplantation site for long‐term in vivo studies can be identified. Even orthotopic engraftment of organoid cultures in the adult does not provide an environment conducive to vascularization and functional differentiation. Previously, we showed that the lymph node offers an alternative transplantation site where mouse metanephroi can differentiate into mature renal structures with excretory, homeostatic, and endocrine functions. Here, we show that the lymph node lends itself well as a niche to also grow human primary kidney rudiments and can additionally be viewed as a platform to interrogate emerging renal organoid cultures. Our study has a wide‐ranging impact for tissue engineering approaches to rebuild functional tissues in vivo including—but not limited to—the kidney.

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Regenerating a kidney in a lymph node

Cited by 6 publications

References 61 publications

Ex Vivo Cell Therapy by Ectopic Hepatocyte Transplantation Treats the Porcine Tyrosinemia Model of Acute Liver Failure

Ex Vivo Cell Therapy by Ectopic Hepatocyte Transplantation Treats the Porcine Tyrosinemia Model of Acute Liver Failure

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

Kidney‐in‐a‐lymph node: A novel organogenesis assay to model human renal development and test nephron progenitor cell fates

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