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Article ; Online: Moving Towards Induced Pluripotent Stem Cell-based Therapies with Artificial Intelligence and Machine Learning.

Coronnello, Claudia / Francipane, Maria Giovanna

2021 Volume 18, Issue 2, Page(s) 559–569

Abstract: The advent of induced pluripotent stem cell (iPSC) technology, which allows to transform one cell type into another, holds the promise to produce therapeutic cells and organs on demand. Realization of this objective is contingent on the ability to ... ...

Abstract	The advent of induced pluripotent stem cell (iPSC) technology, which allows to transform one cell type into another, holds the promise to produce therapeutic cells and organs on demand. Realization of this objective is contingent on the ability to demonstrate quality and safety of the cellular product for its intended use. Bottlenecks and backlogs to the clinical use of iPSCs have been fully outlined and a need has emerged for safer and standardized protocols to trigger cell reprogramming and functional differentiation. Amidst great challenges, in particular associated with lengthy culture time and laborious cell characterization, a demand for faster and more accurate methods for the validation of cell identity and function at different stages of the iPSC manufacturing process has risen. Artificial intelligence-based methods are proving helpful for these complex tasks and might revolutionize the way iPSCs are managed to create surrogate cells and organs. Here, we briefly review recent progress in artificial intelligence approaches for evaluation of iPSCs and their derivatives in experimental studies.
MeSH term(s)	Artificial Intelligence ; Cellular Reprogramming ; Induced Pluripotent Stem Cells ; Machine Learning
Language	English
Publishing date	2021-11-29
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2495577-2
ISSN	2629-3277 ; 1558-6804 ; 1550-8943
ISSN (online)	2629-3277 ; 1558-6804
ISSN	1550-8943
DOI	10.1007/s12015-021-10302-y
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Article ; Online: Zika Virus: A New Therapeutic Candidate for Glioblastoma Treatment.

Francipane, Maria Giovanna / Douradinha, Bruno / Chinnici, Cinzia Maria / Russelli, Giovanna / Conaldi, Pier Giulio / Iannolo, Gioacchin

International journal of molecular sciences

2021 Volume 22, Issue 20

Abstract: Glioblastoma (GBM) is the most aggressive among the neurological tumors. At present, no chemotherapy or radiotherapy regimen is associated with a positive long-term outcome. In the majority of cases, the tumor recurs within 32-36 weeks of initial ... ...

Abstract	Glioblastoma (GBM) is the most aggressive among the neurological tumors. At present, no chemotherapy or radiotherapy regimen is associated with a positive long-term outcome. In the majority of cases, the tumor recurs within 32-36 weeks of initial treatment. The recent discovery that Zika virus (ZIKV) has an oncolytic action against GBM has brought hope for the development of new therapeutic approaches. ZIKV is an arbovirus of the
MeSH term(s)	Brain Neoplasms/pathology ; Brain Neoplasms/therapy ; Glioblastoma/pathology ; Glioblastoma/therapy ; Humans ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Neoplastic Stem Cells/cytology ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/virology ; Neural Stem Cells/cytology ; Neural Stem Cells/metabolism ; Neural Stem Cells/virology ; Oncolytic Virotherapy/methods ; Zika Virus/genetics ; Zika Virus/physiology
Chemical Substances	MIRN34 microRNA, human ; MicroRNAs
Language	English
Publishing date	2021-10-12
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms222010996
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Article ; Online: Generation of Hepatobiliary Cell Lineages from Human Induced Pluripotent Stem Cells: Applications in Disease Modeling and Drug Screening.

Pasqua, Mattia / Di Gesù, Roberto / Chinnici, Cinzia Maria / Conaldi, Pier Giulio / Francipane, Maria Giovanna

International journal of molecular sciences

2021 Volume 22, Issue 15

Abstract: The possibility to reproduce key tissue functions in vitro from induced pluripotent stem cells (iPSCs) is offering an incredible opportunity to gain better insight into biological mechanisms underlying development and disease, and a tool for the rapid ... ...

Abstract	The possibility to reproduce key tissue functions in vitro from induced pluripotent stem cells (iPSCs) is offering an incredible opportunity to gain better insight into biological mechanisms underlying development and disease, and a tool for the rapid screening of drug candidates. This review attempts to summarize recent strategies for specification of iPSCs towards hepatobiliary lineages -hepatocytes and cholangiocytes-and their use as platforms for disease modeling and drug testing. The application of different tissue-engineering methods to promote accurate and reliable readouts is discussed. Space is given to open questions, including to what extent these novel systems can be informative. Potential pathways for improvement are finally suggested.
MeSH term(s)	Animals ; Cell Lineage ; Cellular Reprogramming Techniques/methods ; Digestive System Diseases/metabolism ; Digestive System Diseases/pathology ; Digestive System Diseases/therapy ; Drug Discovery/methods ; Hepatocytes/cytology ; Hepatocytes/metabolism ; Humans ; Induced Pluripotent Stem Cells/cytology ; Precision Medicine/methods ; Tissue Engineering/methods
Language	English
Publishing date	2021-07-30
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22158227
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Article ; Online: Host Lymphotoxin-β Receptor Signaling Is Crucial for Angiogenesis of Metanephric Tissue Transplanted into Lymphoid Sites.

Francipane, Maria Giovanna / Han, Bing / Lagasse, Eric

The American journal of pathology

2019 Volume 190, Issue 1, Page(s) 252–269

Abstract: The mouse lymph node (LN) can provide a niche to grow metanephric kidney to maturity. Here, we show that signaling through the lymphotoxin-β receptor (LTβR) is critical for kidney organogenesis both in the LN and the omentum. By transplanting kidney ... ...

Abstract	The mouse lymph node (LN) can provide a niche to grow metanephric kidney to maturity. Here, we show that signaling through the lymphotoxin-β receptor (LTβR) is critical for kidney organogenesis both in the LN and the omentum. By transplanting kidney rudiments either in the LNs of mice undergoing LTβR antagonist treatment or in the omenta of Ltbr knockout (Ltbr
MeSH term(s)	Animals ; Endothelial Cells/cytology ; Kidney Glomerulus/cytology ; Kidney Glomerulus/transplantation ; Lymphoid Tissue/cytology ; Lymphoid Tissue/metabolism ; Lymphotoxin beta Receptor/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neovascularization, Physiologic ; Organogenesis ; Protein Serine-Threonine Kinases/physiology ; Regeneration ; Signal Transduction ; NF-kappaB-Inducing Kinase
Chemical Substances	Ltbr protein, mouse ; Lymphotoxin beta Receptor ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2019-10-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2943-9
ISSN	1525-2191 ; 0002-9440
ISSN (online)	1525-2191
ISSN	0002-9440
DOI	10.1016/j.ajpath.2019.08.018
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Article ; Online: Establishment and Characterization of 5-Fluorouracil-Resistant Human Colorectal Cancer Stem-Like Cells: Tumor Dynamics under Selection Pressure.

Francipane, Maria Giovanna / Bulanin, Denis / Lagasse, Eric

International journal of molecular sciences

2019 Volume 20, Issue 8

Abstract: 5-Fluorouracil (5-FU) remains the gold standard of first-line treatment for colorectal cancer (CRC). Although it may initially debulk the tumor mass, relapses frequently occur, indicating the existence of cancer cells that are therapy-resistant and are ... ...

Abstract	5-Fluorouracil (5-FU) remains the gold standard of first-line treatment for colorectal cancer (CRC). Although it may initially debulk the tumor mass, relapses frequently occur, indicating the existence of cancer cells that are therapy-resistant and are capable of refueling tumor growth. To identify mechanisms of drug resistance, CRC stem-like cells were subjected to long-term 5-FU selection using either intermittent treatment regimen with the IC50 drug dose or continuous treatment regimen with escalating drug doses. Parental cancer cells were cultivated in parallel. Real-time PCR arrays and bioinformatic tools were used to investigate gene expression changes. We found the first method selected for cancer cells with more aggressive features. We therefore transplanted these cancer cells or parental cells in mice, and again, found that not only did the 5-FU-selected cancer cells generate more aggressive tumors with respect to their parental counterpart, but they also showed a different gene expression pattern as compared to what we had observed in vitro, with
MeSH term(s)	Animals ; Antimetabolites, Antineoplastic/pharmacology ; Apoptosis/drug effects ; Biomarkers ; Cell Cycle/drug effects ; Cell Line, Tumor ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/metabolism ; Colorectal Neoplasms/pathology ; DNA Damage/drug effects ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Resistance, Neoplasm ; Fluorouracil/pharmacology ; Gene Expression Profiling ; Humans ; Mice ; Models, Biological ; Neoplastic Stem Cells/drug effects ; Neoplastic Stem Cells/metabolism ; Signal Transduction/drug effects ; Xenograft Model Antitumor Assays
Chemical Substances	Antimetabolites, Antineoplastic ; Biomarkers ; Fluorouracil (U3P01618RT)
Language	English
Publishing date	2019-04-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms20081817
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Article: Towards Organs on Demand: Breakthroughs and Challenges in Models of Organogenesis.

Francipane, Maria Giovanna / Lagasse, Eric

Current pathobiology reports

2016 Volume 4, Issue 3, Page(s) 77–85

Abstract: In recent years, functional three-dimensional (3D) tissue generation in vitro has been significantly advanced by tissue-engineering methods, achieving better reproduction of complex native organs compared to conventional culture systems. This review will ...

Abstract	In recent years, functional three-dimensional (3D) tissue generation in vitro has been significantly advanced by tissue-engineering methods, achieving better reproduction of complex native organs compared to conventional culture systems. This review will discuss traditional 3D cell culture techniques as well as newly developed technology platforms. These recent techniques provide new possibilities in the creation of human body parts and provide more accurate predictions of tissue response to drug and chemical challenges. Given the rapid advancement in the human induced pluripotent stem cell (iPSC) field, these platforms also hold great promise in the development of patient-specific, transplantable tissues and organs on demand.
Language	English
Publishing date	2016-07-02
Publishing country	United States
Document type	Journal Article
ISSN	2167-485X
ISSN	2167-485X
DOI	10.1007/s40139-016-0111-9
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Article ; Online: Regenerating a kidney in a lymph node.

Francipane, Maria Giovanna / Lagasse, Eric

Pediatric nephrology (Berlin, Germany)

2016 Volume 31, Issue 10, Page(s) 1553–1560

Abstract: The ultimate treatment for end-stage renal disease (ESRD) is orthotopic transplantation. However, the demand for kidney transplantation far exceeds the number of available donor organs. While more than 100,000 Americans need a kidney, only 17,000 people ... ...

Abstract	The ultimate treatment for end-stage renal disease (ESRD) is orthotopic transplantation. However, the demand for kidney transplantation far exceeds the number of available donor organs. While more than 100,000 Americans need a kidney, only 17,000 people receive a kidney transplant each year (National Kidney Foundation's estimations). In recent years, several regenerative medicine/tissue engineering approaches have been exploited to alleviate the kidney shortage crisis. Although these approaches have yielded promising results in experimental animal models, the kidney is a complex organ and translation into the clinical realm has been challenging to date. In this review, we will discuss cell therapy-based approaches for kidney regeneration and whole-kidney tissue engineering strategies, including our innovative approach to regenerate a functional kidney using the lymph node as an in vivo bioreactor.
Language	English
Publishing date	2016-10
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	631932-4
ISSN	1432-198X ; 0931-041X
ISSN (online)	1432-198X
ISSN	0931-041X
DOI	10.1007/s00467-015-3296-y
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Zs.A 2196: Show issues

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Article ; Online: Pluripotent Stem Cells to Rebuild a Kidney: The Lymph Node as a Possible Developmental Niche.

Francipane, Maria Giovanna / Lagasse, Eric

Cell transplantation

2016 Volume 25, Issue 6, Page(s) 1007–1023

Abstract: Kidney disease poses a global challenge. Stem cell therapy may offer an alternative therapeutic approach to kidney transplantation, which is often hampered by the limited supply of donor organs. While specific surface antigen markers have yet to be ... ...

Abstract	Kidney disease poses a global challenge. Stem cell therapy may offer an alternative therapeutic approach to kidney transplantation, which is often hampered by the limited supply of donor organs. While specific surface antigen markers have yet to be identified for the analysis and purification of kidney stem/progenitor cells for research or clinical use, the reprogramming of somatic cells to pluripotent cells and their differentiation into the various kidney lineages might represent a valuable strategy to create a renewable cell source for regenerative purposes. In this review, we first provide an overview of kidney development and explore current knowledge about the role of extra- and intrarenal cells in kidney repair and organogenesis. We then discuss recent advances in the 1) differentiation of rodent and human embryonic stem cells (ESCs) into renal lineages; 2) generation of induced pluripotent stem cells (iPSCs) from renal or nonrenal (kidney patient-derived) adult cells; 3) differentiation of iPSCs into renal lineages; and 4) direct transcriptional reprogramming of adult renal cells into kidney progenitor cells. Finally, we describe the lymph node as a potential three-dimensional (3D) in vivo environment for kidney organogenesis from pluripotent stem cells.
MeSH term(s)	Animals ; Cellular Reprogramming/genetics ; Humans ; Kidney/cytology ; Kidney/embryology ; Lymph Nodes/cytology ; Organogenesis/genetics ; Pluripotent Stem Cells/cytology ; Stem Cell Niche/genetics
Language	English
Publishing date	2016
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1135816-6
ISSN	1555-3892 ; 0963-6897
ISSN (online)	1555-3892
ISSN	0963-6897
DOI	10.3727/096368915X688632
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Article ; Online: Generation of Hepatobiliary Cell Lineages from Human Induced Pluripotent Stem Cells

Mattia Pasqua / Roberto Di Gesù / Cinzia Maria Chinnici / Pier Giulio Conaldi / Maria Giovanna Francipane

International Journal of Molecular Sciences, Vol 22, Iss 8227, p

Applications in Disease Modeling and Drug Screening

2021 Volume 8227

Abstract	The possibility to reproduce key tissue functions in vitro from induced pluripotent stem cells (iPSCs) is offering an incredible opportunity to gain better insight into biological mechanisms underlying development and disease, and a tool for the rapid screening of drug candidates. This review attempts to summarize recent strategies for specification of iPSCs towards hepatobiliary lineages —hepatocytes and cholangiocytes—and their use as platforms for disease modeling and drug testing. The application of different tissue-engineering methods to promote accurate and reliable readouts is discussed. Space is given to open questions, including to what extent these novel systems can be informative. Potential pathways for improvement are finally suggested.
Keywords	iPSCs ; hepatocytes ; cholangiocytes ; disease modeling ; drug testing ; tissue engineering ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Language	English
Publishing date	2021-07-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
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Article ; Online: Fat-associated lymphoid clusters as expandable niches for ectopic liver development.

Han, Bing / Francipane, Maria Giovanna / Cheikhi, Amin / Johnson, Joycelyn / Chen, Fei / Chen, Ruoyu / Lagasse, Eric

Hepatology (Baltimore, Md.)

2022 Volume 76, Issue 2, Page(s) 357–371

Abstract: Background and aims: Hepatocyte transplantation holds great promise as an alternative approach to whole-organ transplantation. Intraportal and intrasplenic cell infusions are primary hepatocyte transplantation delivery routes for this procedure. However, ...

Abstract	Background and aims: Hepatocyte transplantation holds great promise as an alternative approach to whole-organ transplantation. Intraportal and intrasplenic cell infusions are primary hepatocyte transplantation delivery routes for this procedure. However, patients with severe liver diseases often have disrupted liver and spleen architectures, which introduce risks in the engraftment process. We previously demonstrated i.p. injection of hepatocytes as an alternative route of delivery that could benefit this subpopulation of patients, particularly if less invasive and low-risk procedures are required; and we have established that lymph nodes may serve as extrahepatic sites for hepatocyte engraftment. However, whether other niches in the abdominal cavity support the survival and proliferation of the transplanted hepatocytes remains unclear. Approach and results: Here, we showed that hepatocytes transplanted by i.p. injection engraft and generate ectopic liver tissues in fat-associated lymphoid clusters (FALCs), which are adipose tissue-embedded, tertiary lymphoid structures localized throughout the peritoneal cavity. The FALC-engrafted hepatocytes formed functional ectopic livers that rescued tyrosinemic mice from liver failure. Consistently, analyses of ectopic and native liver transcriptomes revealed a selective ectopic compensatory gene expression of hepatic function-controlling genes in ectopic livers, implying a regulated functional integration between the two livers. The lack of FALCs in the abdominal cavity of immunodeficient tyrosinemic mice hindered ectopic liver development, whereas the restoration of FALC formation through bone marrow transplantation restored ectopic liver development in these mice. Accordingly, induced abdominal inflammation increased FALC numbers, which improved hepatocyte engraftment and accelerated the recovery of tyrosinemic mice from liver failure. Conclusions: Abdominal FALCs are essential extrahepatic sites for hepatocyte engraftment after i.p. transplantation and, as such, represent an easy-to-access and expandable niche for ectopic liver regeneration when adequate growth stimulus is present.
MeSH term(s)	Adipose Tissue ; Animals ; Hepatocytes/metabolism ; Liver/pathology ; Liver Diseases/pathology ; Liver Failure/pathology ; Liver Regeneration ; Mice
Language	English
Publishing date	2022-01-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	604603-4
ISSN	1527-3350 ; 0270-9139
ISSN (online)	1527-3350
ISSN	0270-9139
DOI	10.1002/hep.32277
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