Patch grafting of organoids of stem/progenitors into solid organs can correct genetic-based disease states

Zhang, Wencheng; Wauthier, Eliane; Lanzoni, Giacomo; Hani, Homayoun; Yi, Xin; Overi, Diletta; Shi, Lei; Simpson, Sean; Allen, Amanda; Suitt, Carolyn; Ezzell, J. Ashley; Alvaro, Domenico; Cardinale, Vincenzo; Gaudio, Eugenio; Carpino, Guido; Prestwich, Glenn D.; Domínguez‐Bendala, Juan; Gerber, David A.; Mathews, Kyle G.; Piedrahita, Jorge A.; Adin, Christopher A.; Sethupathy, Praveen; He, Zhiying; Reíd, Lola M.

doi:10.1016/j.biomaterials.2022.121647

Cited by 11 publications

(13 citation statements)

References 34 publications

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“…We isolated pBTSCs from porcine biliary trees and generated organoids by protocols established previously for human endodermal stem/progenitors 54 . The cells were maintained in serum-free Kubota’s Medium supplemented with 0.1% hyaluronans, conditions proven successful for ex vivo maintenance of organoids for weeks with the maintenance of stem/progenitor traits in hBTSCs, hHpSCs, and hHBs 54 , 55 . In Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…4b, c ). Detailed descriptions of the differentiation of the organoids under the hormonally defined medium and matrix conditions are given in other publications 54 , 55 .…”

Section: Resultsmentioning

confidence: 99%

“…We used genetic signature studies by which to identify key biomarkers and then used those to locate the niches of these cells within the liver, biliary tree, duodenum, and pancreas in pigs. Proof of their multipotentiality was achieved by isolating the stem/progenitors and assessing their ability to give rise to cells with hepatic as well as pancreatic fates ex vivo under wholly defined culture conditions or with transplantation in vivo using patch grafting strategies for transplantation of organoids into solid organs such as liver and pancreas 54 , 55 .…”

Section: Introductionmentioning

confidence: 99%

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A postnatal network of co-hepato/pancreatic stem/progenitors in the biliary trees of pigs and humans

Zhang

Wang

Lanzoni³

et al. 2023

npj Regen Med

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A network of co-hepato/pancreatic stem/progenitors exists in pigs and humans in Brunner’s Glands in the submucosa of the duodenum, in peribiliary glands (PBGs) of intrahepatic and extrahepatic biliary trees, and in pancreatic duct glands (PDGs) of intrapancreatic biliary trees, collectively supporting hepatic and pancreatic regeneration postnatally. The network is found in humans postnatally throughout life and, so far, has been demonstrated in pigs postnatally at least through to young adulthood. These stem/progenitors in vivo in pigs are in highest numbers in Brunner’s Glands and in PDGs nearest the duodenum, and in humans are in Brunner’s Glands and in PBGs in the hepato/pancreatic common duct, a duct missing postnatally in pigs. Elsewhere in PDGs in pigs and in all PDGs in humans are only committed unipotent or bipotent progenitors. Stem/progenitors have genetic signatures in liver/pancreas-related RNA-seq data based on correlation, hierarchical clustering, differential gene expression and principal component analyses (PCA). Gene expression includes representative traits of pluripotency genes (SOX2, OCT4), endodermal transcription factors (e.g. SOX9, SOX17, PDX1), other stem cell traits (e.g. NCAM, CD44, sodium iodide symporter or NIS), and proliferation biomarkers (Ki67). Hepato/pancreatic multipotentiality was demonstrated by the stem/progenitors’ responses under distinct ex vivo conditions or in vivo when patch grafted as organoids onto the liver versus the pancreas. Therefore, pigs are logical hosts for translational/preclinical studies for cell therapies with these stem/progenitors for hepatic and pancreatic dysfunctions.

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Section: Resultsmentioning

confidence: 99%

“…4b, c ). Detailed descriptions of the differentiation of the organoids under the hormonally defined medium and matrix conditions are given in other publications 54 , 55 .…”

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A postnatal network of co-hepato/pancreatic stem/progenitors in the biliary trees of pigs and humans

Zhang

Wang

Lanzoni³

et al. 2023

npj Regen Med

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“…One interesting aspect of this study worth further developing is the use of the polyurethane scaffold loaded with iLPC organoids, which can serve as a "liver patch" that can be applied on the liver surface. Several other studies have reported liver cell/organoid patches [39,40,41,42,43], and the advantage of such methods is the ability to easily apply this using minimally invasive methods such as laparoscopic surgery, and this can be delivered on multiple areas of the liver surface, and even repeated over time. Most of these studies have used extra-cellular matrix and synthetic hydrogels [39,40], stacked cell sheets [43] or electro-spun fibres [42] to create the patches, however these methods create thin delicate patches that can be difficult to physically manipulate without damaging them.…”

Section: Discussionmentioning

confidence: 99%

The vascularised chamber device significantly enhances the survival of transplanted liver organoids

Shi

Makris

Gerrand

et al. 2023

Preprint

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Organoid transplantation has a promising future in the treatment of liver disease, but a major limitation is the lack of guidance on the most appropriate method for transplantation that maximises organoid survival. Human induced pluripotent stem cell (hiPSC)-derived liver progenitor cell organoids were transplanted into four different transplantation sites in a mouse model of liver disease, using five organoid delivery methods. Organoids were transplanted into the vascularised chamber device established in the groin, or into the liver, spleen, and subcutaneous fat. For organoid transplantations into the liver, organoids were delivered either in Matrigel alone, or in Matrigel and a polyurethane scaffold. At 2 weeks post-transplantation, the vascularised chamber had the highest organoid survival, which was 5.1x higher than the site with second highest survival (p=0.0002), being the intra-hepatic scaffold approach. No organoid survival was observed when delivered into the liver without a scaffold, or when injected into the spleen. Very low survival occurred in transplantations into subcutaneous fat. Animals with the vascularised chamber also had the highest levels of human albumin (0.33 +/- 0.09 ng/mL). This study provides strong evidence supporting the use of the vascularised chamber for future liver organoid transplantation studies, including its translation into clinical therapy.

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“…After that, the Y-miR122-induced hepatocyte-like cells (YR-heps) and HUVECs were cocapsulated in microgels via droplet microfluidic technology, which enhanced both hepatic functions and the vascularization (Scheme B). Patches-assistant transplantation of big grafts on solid organs has shown great potential. − With the assistance of biocompatible and adhesive hyaluronic acid-dopamine (HA-DA) patches, we transplanted the multiple cell-laden microgel grafts in ALF mice. Results showed that the implanted patches could transfer cell-laden microgels effectively to the damaged liver area.…”

Section: Introductionmentioning

confidence: 99%

Microfluidic Fabrication of MicroRNA-Induced Hepatocyte-Like Cells/Human Umbilical Vein Endothelial Cells-Laden Microgels for Acute Liver Failure Treatment

Li,

Wei,

Jin

et al. 2023

ACS Nano

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Patch grafting of organoids of stem/progenitors into solid organs can correct genetic-based disease states

Cited by 11 publications

References 34 publications

A postnatal network of co-hepato/pancreatic stem/progenitors in the biliary trees of pigs and humans

A postnatal network of co-hepato/pancreatic stem/progenitors in the biliary trees of pigs and humans

The vascularised chamber device significantly enhances the survival of transplanted liver organoids

Microfluidic Fabrication of MicroRNA-Induced Hepatocyte-Like Cells/Human Umbilical Vein Endothelial Cells-Laden Microgels for Acute Liver Failure Treatment

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