In Vivo Differentiation of Stem Cell-derived Human Pancreatic Progenitors to Treat Type 1 Diabetes
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In Vivo Differentiation of Stem Cell-derived Human Pancreatic Progenitors to Treat Type 1 Diabetes Mitchell H. Maloy 1 & Matthew A. Ferrer 1 & Natesh Parashurama 1,2,3
# Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Type 1 diabetes mellitus (T1DM) is an autoimmune disease that results from the loss of the pancreatic β-cells. The autoimmune destruction of the β-cells causes the loss of insulin production from the islets of the pancreas, resulting in the loss of blood glucose regulation. This loss of regulation, if not treated, can lead to a plethora of long-term complications in patients. Subsequently, T1DM patients rely on the administration of exogenous insulin sources to maintain their blood glucose levels. In this review, we summarize the history of T1DM therapy and current treatment options. Although treatments for T1DM have progressed substantially, none of the available treatment options allow the patient to live autonomously. Therefore, the challenge to develop a therapy that will fully reverse the disease still remains. A promising field of T1DM therapies is cell replacement therapies derived from human pluripotent stem cells. Here, we specifically review studies that employ stem-cell derived pancreatic progenitors transplanted for in vivo differentiation/maturation and discuss, in detail, the complications that arise post transplantation, including heterogeneity, graft immaturity, and host foreign bodyresponse. We also discuss efforts to induce human stem cell-derived mature β-cells in vitro and compare strategies regarding transplantation of pancreatic progenitors versus mature β-cells cells. Finally, we review key approaches that address critical limitations of in vivo progenitor differentiation including vascularization, oxygenation, and transplant location. The field of islet replacement therapy has made tremendous progress in the last two decades. If the strengths and limitations of the field continue to be identified and addressed, future studies will lead to an ideal treatment for T1DM. Keywords Pluripotent stem cells . Islets . Beta cells . Pancreatic progenitors . Pancreatic endoderm . In vivo . Type 1 diabetes mellitus . Cell therapy . Islet cell transplantation
Introduction In this review, we provide an overview of the scope of treatments for T1DM. To provide context, we first provide a brief overview of pancreatic anatomy, physiology, and pathophysiology. Next, we review the history of T1DM therapy, followed by current approaches to manage T1DM, and limitations of
these techniques. We then discuss islet replacement therapies, pancreas development/organogenesis, and examine the major studies that investigate the transplantation of pancreatic progenitors into mice for in vivo maturation. We outline some of the major problems and solutions associated with in vivo maturation including transplant location, vascularization, and encapsulation. Finally, we summarize the major findings of in vivo maturation studies in a table.
* Natesh Parashurama [email protected] 1
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