Regeneration Of Beta Cells In The Pancreas – In all forms of diabetes, beta cell abundance or function is reduced and therefore the ability of pancreatic cells to regenerate or replenish is a critical requirement. Various lines of research have demonstrated the ability of endocrine as well as acinar, ductal and centroacinar cells to generate new beta cells. Several experimental approaches using injury models, pharmacological or genetic intervention, isolation and in vitro expansion of established progenitors followed by transplantation or combinations thereof have suggested several pathways for β-neogenesis or regeneration. Experimental results have also created controversy regarding the limitations and interpretation of experimental methods and ultimately their physiological significance, especially when considering the differences between mice, the primary animal model, and humans. As a result, consensus has been lacking regarding the relative importance of islet cell proliferation or progenitor differentiation and differentiation of other pancreatic cell types in generating new beta cells. In this review we summarize and evaluate the methods and results of recent experiments related to islet regeneration and address their importance and potential clinical applications in the fight against diabetes.

Insulin-producing β cells are essential for maintaining systemic glucose homeostasis. In both type 1 diabetes (T1D) and type 2 diabetes (T2D), reduction and/or deficiency of beta cells leads to insulin insufficiency and hyperglycemia. T1D is the result of autoimmune destruction of β cells. In the clinical onset of T1D, there are still β-cells remaining, but the abundance of β-cells decreases further with increasing duration of T1D. However, many people with chronic T1D continue to secrete insulin, indicating the persistence of some beta cells. In T2D, the combination of insulin resistance due to obesity and impaired beta cell function leads to hyperglycemia. With increasing duration of T2D, β-cell abundance and function gradually decrease. Therefore, in both types of diabetes, there is a great need to restore or increase β cell mass (1). In this review, we compare and contrast two primary mechanisms by which β cell mass can increase: 1) differentiation of progenitor/stem cells or differentiation of other types of pancreatic cells into new β cells; and 2) stimulation of proliferation of remaining β cells. These two methods are discussed in relation to their physiological importance and the Advantages and Disadvantages of each discussed below and in Table 1. Although they are presented as two different processes, in fact, both can play an important role in restoring beta cell abundance. Before discussing these procedures, we first review important experimental issues.

Regeneration Of Beta Cells In The Pancreas

Regeneration Of Beta Cells In The Pancreas

First, proliferation and differentiation are key processes in establishing and maintaining beta core mass. However, for studies related to diabetes, it is recommended to start with a decrease in beta cell mass that later recovers as what determines the recovery may differ from the baseline indicators of beta cell mass. Several experimental methods can be used to reduce beta cell abundance and the method taken can affect the results of β cell recovery tests. For example, chemical ablation of β-cells with toxins such as streptozotocin or alloxan can affect not only β-cells, but also early cells involved in β-molecule regeneration. In contrast, the genetic approach, with deletion of the gene leading to decreased beta cell abundance, is the product of irreversible genetic changes that may not be a true representation of the genetic environment of the original disease state.

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Second, while studying human tissue is important, there are many limitations and challenges. Although great strides have been made in the acquisition, processing, and operation of human pancreatic islets in recent years, human islets available for research are still scarce. Among tissues procured for research, there is great variability in physiological responses due to genetic differences in different parts of the population. Efforts to address this deficiency and genetic variation have used the directed differentiation of human stem cells into islet cells in culture. These methods have achieved some success, but this is still a new area of ​​research and suffers from limitations seen in many static culture models.

Third, rats have a lot of power but some experimental limitations. Cre recombinase reporter lines driven by the insulin or fluorescence promoter, by deletion of a β-cell target gene or expression of a β-cell-specific reporter, have shown differences in β-cell specificity and unexpected effects. Furthermore, although rat β cells show greater regenerative capacity than human β cells, their regeneration is still difficult to stimulate. Many methods used to assess β-cell regeneration in mice, such as high-fat diet or pancreatic fractionation, represent acute stresses that may not be physiologically relevant to human islets, even those under physiological stress that result in loss of beta cells in diabetes.

Fourth, there are significant differences between human and mouse islets that must be considered when extrapolating mouse islet studies to humans. Mouse islets have a different architecture than human islets, with α cells outside the islet surrounding the nucleus of β cells. In contrast, human islets have overlapping α and β cells, implying differences in intercellular communication. Mouse islets have a higher β:α cell ratio (approximately 7:1) than human islets, where the β:α ratio is closer to 2:1. Mouse islet cells have shown greater specificity with respect to proliferation, differentiation and differentiation than human islets. As discussed below, many mitogenic pathways in β cells were identified in mouse experiments. Unfortunately, targeting individual pathways in human beta cells was not sufficient to stimulate proliferation as much as it did in mice. It was only when integrative techniques were used that human β-cells reached a level of proliferation that could restore beta-cell abundance in the diabetic state. All these differences, among others, indicate that caution is needed when translating results from mice to humans.

Taken together, these empirical factors represent challenges that must be overcome when evaluating beta cell regeneration techniques. Consideration of the developmental nature of beta cells and their lineage relationships with other pancreatic cell types is also important as it may shed light on the molecular mechanisms of β cell proliferation and regeneration in the adult. All pancreatic cell types are derived from the same number of pancreatic progenitors that develop in the anterior region of the developing embryo. Pancreatic progenitors are defined by the expression of the transcription factors PDX1, SOX9 and PTF1A and, as development progresses, form a branching epithelium. Acinar progenitors are progressively restricted to the ends of this epithelium while stem cells are bipotent endocrine/ductile progenitors. All endocrine progenitors appear in the stem as NGN3

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Cells and migrate into the mesenchyme to form islets that contain insulin producing β-cells (2, 3). Germ differentiation provides a proliferative space that increases the abundance of beta cells during fetal development and early neonatal development. The ability of β cells to proliferate decreases with age. The beta cells of fetuses and infants proliferate at the highest rates while the proliferation of beta cells in adults, under normal physiological conditions, is very low meaning that the majority of β cells are deposited in early adolescence.

With these experimental considerations in mind, the aim of this review will be to describe in detail the current understanding of the molecular and cellular mechanisms involved in β-cell regeneration. Previous attempts at β-cell regeneration therapy have been reviewed recently (1, 4, 5). Our goal is not to repeat these details, but rather, we hope the reader will gain a deeper view of the possibilities of β-cell regeneration and a novel understanding of the underlying molecular and cellular mechanisms. This discussion is accompanied by our assessment of the pros and cons of targeting these different mechanisms of beta cell regeneration in hopes of inspiring new and innovative ideas regarding potential therapies for beta cell regeneration.

The challenge of adult beta cell regeneration is to return pancreatic cell types to an early developmental state that will allow them to regain their ability to proliferate and differentiate into fully functional beta cells. The generation of resident or stem cells would be an additional way to restore β-molecule function.

Regeneration Of Beta Cells In The Pancreas

After differentiation from progenitors during fetal pancreatic development, early β cells expand through proliferation (6). Although it is important to increase beta cell abundance in the fetal and infant pancreas, beta cell proliferation declines rapidly into early adolescence and is absent in adulthood. The lack of proliferative capacity in adult beta cells becomes a problem in people with diabetes because both T1D and T2D are associated with loss of beta cells at some point during their progression. For this reason, much emphasis in diabetes research has been placed on understanding beta-cell proliferation during development and stimulating β-cell proliferation in adults.

Pdf] Crosstalk Between Macrophages And Pancreatic β Cells In Islet Development, Homeostasis And Disease

Previous studies in mice showed an important role for β cell proliferation in the establishment of adult β cell mass (6, 7). This suggests that it is the systemic environment in young animals that allows the expansion of β-cell mass through proliferation. The proliferative capacity observed in these early beta cells is lost in adults due to a decrease in humoral stimulatory factors (8), increased inhibition of the cyclin-dependent kinase, p16.

, expression (9) and decreased response to PDGF

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