Proteomic analysis of decellularized pancreatic matrix identifies collagen V as a critical regulator for islet organogenesis from human pluripotent stem cells

Bi, Hong‐Yan; Ye, Kaiming; Jin, Sha

doi:10.1016/j.biomaterials.2019.119673

Cited by 79 publications

(97 citation statements)

References 53 publications

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“…Pancreatic tissues derived from iPSC cultured in 3D bioprinted inks primarily composed of dpECM had increased Pdx1, insulin, and glucagon expression compared to collagen controls (Kim et al, 2019). Cell culture with the addition of collagen V, which was present in dpECM but not in Matrigel, enhanced islet organoid generation and glucose-responsive function (Bi et al, 2020). Overall, designing cell culture systems which recapitulate the in vivo ECM protein landscape could have significant impact to produce functional PSCderived beta cells.…”

Section: Biochemical Effects Of Ecm Proteinsmentioning

confidence: 99%

Developmentally-Inspired Biomimetic Culture Models to Produce Functional Islet-Like Cells From Pluripotent Precursors

Tran

Moraes

Hoesli

2020

Front. Bioeng. Biotechnol.

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Insulin-producing beta cells sourced from pluripotent stem cells hold great potential as a virtually unlimited cell source to treat diabetes. Directed pancreatic differentiation protocols aim to mimic various stimuli present during embryonic development through sequential changes of in vitro culture conditions. This is commonly accomplished by the timed addition of soluble signaling factors, in conjunction with cell-handling steps such as the formation of 3D cell aggregates. Interestingly, when stem cells at the pancreatic progenitor stage are transplanted, they form functional insulinproducing cells, suggesting that in vivo microenvironmental cues promote beta cell specification. Among these cues, biophysical stimuli have only recently emerged in the context of optimizing pancreatic differentiation protocols. This review focuses on studies of cell-microenvironment interactions and their impact on differentiating pancreatic cells when considering cell signaling, cell-cell and cell-ECM interactions. We highlight the development of in vitro cell culture models that allow systematic studies of pancreatic cell mechanobiology in response to extracellular matrix proteins, biomechanical effects, soluble factor modulation of biomechanics, substrate stiffness, fluid flow and topography. Finally, we explore how these new mechanical insights could lead to novel pancreatic differentiation protocols that improve efficiency, maturity, and throughput.

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Section: Biochemical Effects Of Ecm Proteinsmentioning

confidence: 99%

Developmentally-Inspired Biomimetic Culture Models to Produce Functional Islet-Like Cells From Pluripotent Precursors

Tran

Moraes

Hoesli

2020

Front. Bioeng. Biotechnol.

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“…The enhanced expression of a PDX1 – /NKX6.1 + population can be achieved by manipulating the re-plating density of endodermal cells, and further differentiation into endocrine progenitors [ 27 ]. Recently, it was discovered that blending type V collagen with Matrigel as coating substrates for iPSC endocrine differentiation can significantly augment the gene expressions of Pdx1 and Nkx6.1, leading to glucose-responsive insulin and glucagon secretion in iPSC-derived islet organoids [ 8 ]. In another study, it was found that the spontaneous clustering of cells, measuring less than 500 µm in diameter, can significantly increase the expression of NKX6.1 and PDX1 compared to cells cultured in monolayers, although the mechanisms underlying the effect of aggregate size on these key marker expressions is unknown [ 28 ].…”

Section: Molecules Promoting the Generation Of Functional β-Cells mentioning

confidence: 99%

“…Hence, the generation of α-cells from hESCs has been studied as well. Current hPSC differentiation protocols permitted the generation of both insulin-secreting β-cells and glucagon-secreting α-cells in a pancreatic endocrine lineage by using molecules to control signaling pathways, as shown in Figure 1 [ 2 , 3 , 7 , 8 , 62 ]. For instance, applying LDN193189 (LDN), an inhibitor of BMP signaling, to the middle stage of the differentiation process could suppress the expression of NKX6.1 and induce the development of α-cells [ 63 ] ( Figure 1 , Table 2 ).…”

Section: Molecules Critical For the Generation Of Functional α-Celmentioning

confidence: 99%

“…For instance, applying LDN193189 (LDN), an inhibitor of BMP signaling, to the middle stage of the differentiation process could suppress the expression of NKX6.1 and induce the development of α-cells [ 63 ] ( Figure 1 , Table 2 ). As a result, cells were secreting both insulin and glucagon at the end of hESC differentiation [ 7 , 8 ]. In addition, phorbol 12,13-dibutyrate (PDBu) is an activator of protein kinase C (PKC).…”

Section: Molecules Critical For the Generation Of Functional α-Celmentioning

confidence: 99%

“…In the past two decades, extensive efforts have been made to derive insulin-secreting cells and islet-like organoids from human embryonic stem cells (hESCs) and/or human induced pluripotent stem cells (iPSCs) in vitro [ 2 , 3 , 4 , 5 , 6 ]. Recently, the generation of islet organoids consisting of multiple hormone-secreting islet cell types from human pluripotent stem cell (hPSC) differentiation, including both iPSCs and hESCs, has been reported [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

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Signaling Molecules Regulating Pancreatic Endocrine Development from Pluripotent Stem Cell Differentiation

Huang

Bader

Jin

2020

IJMS

Self Cite

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Diabetes is one of the leading causes of death globally. Currently, the donor pancreas is the only source of human islets, placing extreme constraints on supply. Hence, it is imperative to develop renewable islets for diabetes research and treatment. To date, extensive efforts have been made to derive insulin-secreting cells from human pluripotent stem cells with substantial success. However, the in vitro generation of functional islet organoids remains a challenge due in part to our poor understanding of the signaling molecules indispensable for controlling differentiation pathways towards the self-assembly of functional islets from stem cells. Since this process relies on a variety of signaling molecules to guide the differentiation pathways, as well as the culture microenvironments that mimic in vivo physiological conditions, this review highlights extracellular matrix proteins, growth factors, signaling molecules, and microenvironments facilitating the generation of biologically functional pancreatic endocrine cells from human pluripotent stem cells. Signaling pathways involved in stepwise differentiation that guide the progression of stem cells into the endocrine lineage are also discussed. The development of protocols enabling the generation of islet organoids with hormone release capacities equivalent to native adult islets for clinical applications, disease modeling, and diabetes research are anticipated.

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Engineered Biomaterials for Enhanced Function of Insulin‐Secreting β‐Cell Organoids

Hunckler

Garcı́a

2020

Adv Funct Materials

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Insulin-secreting β-cell organoids comprise many types of cells, including primary islets, pseudoislets, immortalized cell lines, and stem cell-derived aggregates. Successful maintenance and long-term culture of these β-cell organoids are critical for many translational applications, such as patient-specific disease modeling, drug screening, understanding β-cell physiology, and cell-based therapies to treat diabetes. Due to the mechanical and chemical insult to islets during isolation, islet viability and function are decreased. Partial restoration of the islet microenvironment through engineered biomaterials can improve islet survival and function in in vitro culture and in vivo transplantation. Natural and synthetic biomaterials can be engineered to improve the function of β-cell organoids and promote maturation of stem cell-derived β-cell organoids. Improved function and maturation of β-cell organoids will likely lead to improved transplant outcomes, but will also enable better models for physiology, disease modeling, and toxicology studies for type 1 and type 2 diabetes mellitus. The goal of this review is to highlight the diverse array of biomaterials used to enhance the in vitro and in vivo function and maturation of β-cell organoids.

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Proteomic analysis of decellularized pancreatic matrix identifies collagen V as a critical regulator for islet organogenesis from human pluripotent stem cells

Cited by 79 publications

References 53 publications

Developmentally-Inspired Biomimetic Culture Models to Produce Functional Islet-Like Cells From Pluripotent Precursors

Developmentally-Inspired Biomimetic Culture Models to Produce Functional Islet-Like Cells From Pluripotent Precursors

Signaling Molecules Regulating Pancreatic Endocrine Development from Pluripotent Stem Cell Differentiation

Engineered Biomaterials for Enhanced Function of Insulin‐Secreting β‐Cell Organoids

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