Publications by authors named "Najah Therese Nassif"

2 Publications

  • Page 1 of 1

Expansion of Murine MSC Impairs Transcription Factor-Induced Differentiation into Pancreatic -Cells.

Stem Cells Int 2019 10;2019:1395301. Epub 2019 Mar 10.

The School of Life Sciences and Centre for Health Technologies, Faculty of Science, University of Technology Sydney, Sydney, Australia.

Combinatorial gene and cell therapy as a means of generating surrogate -cells has been investigated for the treatment of type 1 diabetes (T1D) for a number of years with varying success. One of the limitations of current cell therapies for T1D is the inability to generate sufficient quantities of functional transplantable insulin-producing cells. Due to their impressive immunomodulatory properties, in addition to their ease of expansion and genetic modification , mesenchymal stem cells (MSCs) are an attractive alternative source of adult stem cells for regenerative medicine. To overcome the aforementioned limitation of current therapies, we assessed the utility of expanded bone marrow-derived murine MSCs for their persistence in immune-competent and immune-deficient animal models and their ability to differentiate into surrogate -cells. CD45/Ly6 murine MSCs were isolated from the bone marrow of nonobese diabetic (NOD) mice and nucleofected to express the bioluminescent protein, . The persistence of a subcutaneous (s.c.) transplant of -expressing MSCs was assessed in immune-competent (NOD) ( = 4) and immune-deficient (NOD/) ( = 4) animal models of diabetes. -expressing MSCs persisted for 2 and 12 weeks, respectively, in NOD and NOD/ mice. expanded MSCs were transduced with the HMD lentiviral vector (MOI = 10) to express furin-cleavable human insulin () and murine and . This was followed by the characterization of pancreatic transdifferentiation via reverse transcriptase polymerase chain reaction (RT-PCR) and static and glucose-stimulated insulin secretion (GSIS). -expressing MSCs were assessed for their ability to reverse diabetes after transplantation into streptozotocin- (STZ-) diabetic NOD/ mice ( = 5). Transduced MSCs did not undergo pancreatic transdifferentiation, as determined by RT-PCR analyses, lacked glucose responsiveness, and upon transplantation did not reverse diabetes. The data suggest that expanded MSCs lose their multipotent differentiation potential and may be more useful as gene therapy targets prior to expansion.
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March 2019

CRISPR-targeted genome editing of mesenchymal stem cell-derived therapies for type 1 diabetes: a path to clinical success?

Stem Cell Res Ther 2017 03 9;8(1):62. Epub 2017 Mar 9.

The School of Life Sciences, Chronic Disease Solutions Team and the Centre for Health Technologies, University of Technology Sydney, PO Box 123, Broadway, NSW, 2007, Australia.

Due to their ease of isolation, differentiation capabilities, and immunomodulatory properties, the therapeutic potential of mesenchymal stem cells (MSCs) has been assessed in numerous pre-clinical and clinical settings. Currently, whole pancreas or islet transplantation is the only cure for people with type 1 diabetes (T1D) and, due to the autoimmune nature of the disease, MSCs have been utilised either natively or transdifferentiated into insulin-producing cells (IPCs) as an alternative treatment. However, the initial success in pre-clinical animal models has not translated into successful clinical outcomes. Thus, this review will summarise the current state of MSC-derived therapies for the treatment of T1D in both the pre-clinical and clinical setting, in particular their use as an immunomodulatory therapy and targets for the generation of IPCs via gene modification. In this review, we highlight the limitations of current clinical trials of MSCs for the treatment of T1D, and suggest the novel clustered regularly interspaced short palindromic repeat (CRISPR) gene-editing technology and improved clinical trial design as strategies to translate pre-clinical success to the clinical setting.
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March 2017