Treatment of newborn G6pc mice with bone marrow-derived myelomonocytes induces liver repair

Resaz, Roberta; Emionite, Laura; Vanni, Cristina; Astigiano, Simonetta; Puppo, Maura; Lavieri, Rosa; Segalerba, Daniela; Pezzolo, Annalisa; Bosco, Maria Carla; Oberto, Alessandra; Eva, Carola; Chou, Janice Y.; Varesio, Luigi; Barbieri, Ottavia; Eva, Alessandra

doi:10.1016/j.jhep.2011.02.033

Cited by 8 publications

(9 citation statements)

References 31 publications

(66 reference statements)

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“…Despite promising, some complications might still occur after stem cell based therapies, including renal complications. New-born G6PC knock-out mice treated with bone marrow-derived myelomonocytic cells displayed restored G6Pase activity and improved liver functional parameters, without amelioration of renal involvement [ 51 ]. Similarly, there is concern that hepatic adenoma and carcinoma might develop in the cells with a defect G6PT/G6Pase complex with the use of cell-based therapies that do not replace all patient cells.…”

Section: Discussionmentioning

confidence: 99%

Liver transplantation in glycogen storage disease type I

Boers

Visser

Smit

et al. 2014

Orphanet J Rare Dis

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Glycogen storage disease type I (GSDI), an inborn error of carbohydrate metabolism, is caused by defects in the glucose-6-transporter/glucose-6-phosphatase complex, which is essential in glucose homeostasis. Two types exist, GSDIa and GSDIb, each caused by different defects in the complex. GSDIa is characterized by fasting intolerance and subsequent metabolic derangements. In addition to these clinical manifestations, patients with GSDIb suffer from neutropenia with neutrophil dysfunction and inflammatory bowel disease.With the feasibility of novel cell-based therapies, including hepatocyte transplantations and liver stem cell transplantations, it is essential to consider long term outcomes of liver replacement therapy. We reviewed all GSDI patients with liver transplantation identified in literature and through personal communication with treating physicians. Our review shows that all 80 GSDI patients showed improved metabolic control and normal fasting tolerance after liver transplantation. Although some complications might be caused by disease progression, most complications seemed related to the liver transplantation procedure and subsequent immune suppression. These results highlight the potential of other therapeutic strategies, like cell-based therapies for liver replacement, which are expected to normalize liver function with a lower risk of complications of the procedure and immune suppression.

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Section: Discussionmentioning

confidence: 99%

Liver transplantation in glycogen storage disease type I

Boers

Visser

Smit

et al. 2014

Orphanet J Rare Dis

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“…Although these animals have been used to develop somatic gene therapies that show promise as being efficacious treatments for GSD-1a (Chou et al, 2010; Resaz et al, 2011), they are unsuitable for long-term studies on disease-associated organ degeneration owing to their early death if untreated. Therefore, there is the need for alternative animal models for GSD-1a for studying both long-term liver degeneration and long-term effects of new therapeutic approaches.…”

Section: Discussionmentioning

confidence: 99%

Development of hepatocellular adenomas and carcinomas in mice with liver-specific G6Pase-α deficiency

Resaz

Vanni

Segalerba

et al. 2014

Disease Models &Amp; Mechanisms

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Glycogen storage disease type 1a (GSD-1a) is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α), and is characterized by impaired glucose homeostasis and a high risk of developing hepatocellular adenomas (HCAs). A globally G6Pase-α-deficient (G6pc−/−) mouse model that shows pathological features similar to those of humans with GSD-1a has been developed. These mice show a very severe phenotype of disturbed glucose homeostasis and rarely live beyond weaning. We generated liver-specific G6Pase-α-deficient (LS‑G6pc−/−) mice as an alternative animal model for studying the long-term pathophysiology of the liver and the potential treatment strategies, such as cell therapy. LS‑G6pc−/− mice were viable and exhibited normal glucose profiles in the fed state, but showed significantly lower blood glucose levels than their control littermates after 6 hours of fasting. LS‑G6pc−/− mice developed hepatomegaly with glycogen accumulation and hepatic steatosis, and progressive hepatic degeneration. Ninety percent of the mice analyzed developed amyloidosis by 12 months of age. Finally, 25% of the mice sacrificed at age 10–20 months showed the presence of multiple HCAs and in one case late development of hepatocellular carcinoma (HCC). In conclusion, LS‑G6pc−/− mice manifest hepatic symptoms similar to those of human GSD-1a and, therefore, represent a valid model to evaluate long-term liver pathogenesis of GSD-1a.

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“…Previous studies have demonstrated the efficacy of gene therapy in treating mouse models of GSD-Ia (15,17,18). In addition, alternative therapies, including bone marrow-derived myelomonocyte transplantation, may have the potential to restore normal liver function (19).…”

Section: Discussionmentioning

confidence: 99%

Molecular genetic analysis and phenotypic characteristics of a consanguineous family with glycogen storage disease type Ia

Lü

Li-yin

et al. 2016

Molecular Medicine Reports

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Glycogen storage disease type‑Ia (GSD‑Ia) is a rare autosomal recessive disease caused by a mutation in the gene encoding glucose‑6‑phosphate‑α (G6PC). The present study reported the case of a 3‑month‑old female Chinese patient with GSD‑Ia born to consanguineous parents. The aim of the present study was to identify the precise mutation of the G6PC gene associated with this family and to describe the phenotypic characteristics of the patient. A comprehensive examination was performed on the patient, including physical examination, vein blood gas analysis, abdominal sonography and biochemical analyses. In addition, gene sequencing was performed on the coding region of the G6PC gene to identify the mutation. The patient was diagnosed with GSD‑Ia and a G6PC missense mutation of c.518T>C (p.L173P) located in a highly conserved area was identified. The mutation is in a non‑helical region of the protein, which previous studies have suggested should result in a lesser effect on G6PC enzymatic activity and milder phenotypic characteristics compared with mutations located in helical regions. However, the severity of the disease phenotype in the subject of the present study was inconsistent with that predicted from her genotype. The patient suffered from serious hypoglycemia, lactic acidosis, increased triglycerides, hepatic dysfunction, clear hepatomegaly and nephromegaly. The incidence of the p.L173P mutation may be relatively high in the Chinese population. Knowledge of the various phenotypic presentations of the p.L173P mutation may beneficial for future investigations.

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Treatment of newborn G6pc mice with bone marrow-derived myelomonocytes induces liver repair

Abstract: Our data indicate that bone marrow-derived myelomonocytic cell transplant may represent an effective way to achieve liver reconstitution of highly degenerated livers in newborn animals.

Cited by 8 publications

References 31 publications

Liver transplantation in glycogen storage disease type I

Liver transplantation in glycogen storage disease type I

Development of hepatocellular adenomas and carcinomas in mice with liver-specific G6Pase-α deficiency

Molecular genetic analysis and phenotypic characteristics of a consanguineous family with glycogen storage disease type Ia

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