The Human Endocrine Pancreas: New Insights on Replacement and Regeneration

Domínguez‐Bendala, Juan; Lanzoni, Giacomo; Klein, Dagmar; Álvarez-Cubela, Silvia; Pastori, Ricardo L.

doi:10.1016/j.tem.2015.12.003

Cited by 28 publications

(11 citation statements)

References 67 publications

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“…We acknowledge that the β-like cells generated in our study are not as competent as native β cells. This observation was also probably compounded by the fact that effective differentiation of pancreatic progenitors into mature β cells remains a bottleneck in the field ( Domínguez-Bendala et al, 2016 ) and the lack of optimization in this particular setting. It is important to emphasize that our study was aimed at establishing proof of principle and not the generation of fully functional, terminally differentiated cells.…”

Section: Discussionmentioning

confidence: 99%

P2RY1/ALK3-Expressing Cells within the Adult Human Exocrine Pancreas Are BMP-7 Expandable and Exhibit Progenitor-like Characteristics

et al. 2018

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SUMMARYTreatment of human pancreatic non-endocrine tissue with Bone Morphogenetic Protein 7 (BMP-7) leads to the formation of glucose-responsive β-like cells. Here, we show that BMP-7 acts on extrainsular cells expressing PDX1 and the BMP receptor activin-like kinase 3 (ALK3/BMPR1A). In vitro lineage tracing indicates that ALK3+ cell populations are multipotent. PDX1+/ALK3+ cells are absent from islets but prominently represented in the major pancreatic ducts and pancreatic duct glands. We identified the puri-nergic receptor P2Y1 (P2RY1) as a surrogate surface marker for PDX1. Sorted P2RY1+/ALK3bright+ cells form BMP-7-expandable colonies characterized by NKX6.1 and PDX1 expression. Unlike the negative fraction controls, these colonies can be differentiated into multiple pancreatic lineages upon BMP-7 withdrawal. RNA-seq further corroborates the progenitor-like nature of P2RY1+/ALK3bright+ cells and their multilineage differentiation potential. Our studies confirm the existence of progenitor cells in the adult human pancreas and suggest a specific anatomical location within the ductal and glandular networks.

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Section: Discussionmentioning

confidence: 99%

P2RY1/ALK3-Expressing Cells within the Adult Human Exocrine Pancreas Are BMP-7 Expandable and Exhibit Progenitor-like Characteristics

et al. 2018

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“…It might reflect the heterogeneous nature of donor islets as it is understood better now. b cells may be produced from ª 2016 Japanese Society of Developmental Biologists human stem cells in vitro, but it is difficult to achieve controlled insulin secretion upon glucose stimulation (Dominguez-Bendala et al 2016). The complex way of in vivo development through fusion might be referred to in vitro preparations of biologically competent islets.…”

Section: Discussionmentioning

confidence: 99%

Human pancreatic islets develop through fusion of distinct β and α/δ islets

Lee

2016

Dev Growth Differ

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Human pancreatic islets show unique architecture in which α and δ cells are mostly at the peripheral and perivascular areas. It has remained unknown how such prototype is realized in every islet. Here, I report that fetal islets develop first in two distinct types consisting of β or α/δ cells, respectively. The α/δ islets are variable in shape, composed of α and δ cells evenly intermixed. They are vascularized better but encapsulated poorer than β islets in general. During the development, the β and α/δ islets adjoin and fuse with each other in such a way that α and δ cells form a crescent on β cells and, then, progress to encompass and encroach into β cells. Most mature-form islets appear to develop through the fusion. Islets at various stages of fusion are present concurrently until late gestation, suggesting that the islet fusion is an ongoing developmental process. The α/δ islets appear to play a primary role for the process, approaching toward the fusion partner actively. Direct connection is present between the α/δ islets and neural ganglia undergoing active neurogenesis, suggesting an organ-wide neuroendocrine network development. The fusion of precursor islets appears to be a principle of human pancreatic development providing the prototype of mature islets. The complex development might be a reference for in vitro reproduction of biologically competent islets.

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“…In both cases, current therapies aim at controlling glucose levels by providing insulin, increasing insulin secretion, or improving insulin sensitivity; however, they do not regenerate β-cell mass, which is necessary to have remission. Only regenerative or replacing therapies can resolve the problem (for a review, see [4]).…”

Section: Introductionmentioning

confidence: 99%

Shaping Pancreatic β-Cell Differentiation and Functioning: The Influence of Mechanotransduction

Galli

Marku

Marciani

et al. 2020

Cells

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Embryonic and pluripotent stem cells hold great promise in generating β-cells for both replacing medicine and novel therapeutic discoveries in diabetes mellitus. However, their differentiation in vitro is still inefficient, and functional studies reveal that most of these β-like cells still fail to fully mirror the adult β-cell physiology. For their proper growth and functioning, β-cells require a very specific environment, the islet niche, which provides a myriad of chemical and physical signals. While the nature and effects of chemical stimuli have been widely characterized, less is known about the mechanical signals. We here review the current status of knowledge of biophysical cues provided by the niche where β-cells normally live and differentiate, and we underline the possible machinery designated for mechanotransduction in β-cells. Although the regulatory mechanisms remain poorly understood, the analysis reveals that β-cells are equipped with all mechanosensors and signaling proteins actively involved in mechanotransduction in other cell types, and they respond to mechanical cues by changing their behavior. By engineering microenvironments mirroring the biophysical niche properties it is possible to elucidate the β-cell mechanotransductive-regulatory mechanisms and to harness them for the promotion of β-cell differentiation capacity in vitro.

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The Human Endocrine Pancreas: New Insights on Replacement and Regeneration

Cited by 28 publications

References 67 publications

P2RY1/ALK3-Expressing Cells within the Adult Human Exocrine Pancreas Are BMP-7 Expandable and Exhibit Progenitor-like Characteristics

P2RY1/ALK3-Expressing Cells within the Adult Human Exocrine Pancreas Are BMP-7 Expandable and Exhibit Progenitor-like Characteristics

Human pancreatic islets develop through fusion of distinct β and α/δ islets

Shaping Pancreatic β-Cell Differentiation and Functioning: The Influence of Mechanotransduction

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