Evidence for the presence of stem cell-like progenitor cells in human adult pancreas

Zhao, Min; Amiel, Stephanie A.; Christie, Michael R.; Muiesan, Paolo; Srinivasan, Parthi; Littlejohn, W.; Rela, Mohamed; Arno, Matthew; Heaton, Nigel; Huang, Guo Cai

doi:10.1677/joe-07-0436

Cited by 47 publications

(35 citation statements)

References 37 publications

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“…Cells expressing OCT4 termed 'very small embryonic-like stem cells' have recently been isolated from murine pancreas (Zuba-Surma et al 2009), and it has been proposed that these may provide a quiescent pool of stem cells for replenishing tissue-specific progenitors in times of extensive tissue injury. The presence of cells expressing OCT4 and SOX2 in unmanipulated human pancreas has previously been reported (Zhao et al 2007). In this study, we have confirmed the size of OCT4-positive cells as only w1 .…”

Section: Discussionsupporting

confidence: 87%

“…In established adults (Manesso et al 2009) and in response to injury (Dor et al 2004, Xu et al 2008, however, the potential for non-b-cell sources including facultative endocrine progenitor cells has been proposed in convincing studies. Several groups have identified and isolated putative stem cells from adult pancreas (Seaberg et al 2004, Suzuki et al 2004, Eberhardt et al 2006, but the expression of the pluripotency-associated embryonic stem (ES) cell markers has only been reported in exploratory studies on mice (Zuba-Surma et al 2009) and unmanipulated human pancreas (Zhao et al 2007, Al-Turaifi et al 2008.…”

Section: Introductionmentioning

confidence: 99%

“…These proteins are essential for generation and maintenance of the ES cell identity by forming an auto-regulatory network that controls the expression and repression of pluripotency-and differentiation-associated genes respectively (Boyer et al 2005). Although a key pluripotency mediator in ES cells, several studies have reported the expression of OCT4 in unmanipulated and cultured somatic tissues (Zhao et al 2007, Kristensen et al 2010, Pacini et al 2010.…”

Section: Introductionmentioning

confidence: 99%

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Pluripotency-associated stem cell marker expression in proliferative cell cultures derived from adult human pancreas

White

Alturaifi²,

Holliman³

et al. 2011

Journal of Endocrinology

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The source of new b-cells in adult human pancreas remains incompletely elucidated with recent studies on rodents providing evidence for neogenesis from progenitor cells in addition to self-replication. The aim of this study was to investigate the expression of pluripotency-associated stem cell markers in proliferative cultures derived from adult human pancreas. Human pancreatic tissue was obtained from deceased donors following ethical approval and relative consent. Isletenriched fraction was separated from the retrieved organ by digestion and density gradient centrifugation. Dissociated cells were seeded in adherent culture forming proliferative 'islet survivor cells' (ISCs). These were characterised at fifth passage by RT-PCR, immunofluorescence staining, FACS, western blot and transfection studies with an OCT4 promoter-driven reporter. Nuclear expression of the pluripotency-associated stem cell marker complex OCT4/SOX2/NANOG was confirmed in ISCs. The phenotype constituted w8% of the overall population. OCT4 biosynthesis was confirmed by western blot and activation of an exogenous OCT4 promoter. Co-expression of pluripotency-associated markers has been confirmed in proliferative primary cells derived from adult human pancreas. Further studies are required to elucidate whether these cells possess functional stem cell characteristics and assess potential for differentiation into pancreatic cell lineages including new b-cells.

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Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pluripotency-associated stem cell marker expression in proliferative cell cultures derived from adult human pancreas

White

Alturaifi²,

Holliman³

et al. 2011

Journal of Endocrinology

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“…the generation of β cells from undifferentiated or partially differentiated precursors, may also be involved in the maintenance of β cell mass . Very little is known about these putative stem cells, which may reside within the islet itself (Zulewski et al 2001;Petropavlovskaia & Rosenberg 2002)or in the pancreatic ducts (Bonner-Weir et al 2000;Zhao et al 2007). The convincing data demonstrating that β cells maintain their mass through the replication of preexisting β cells (Dor et al 2004;Teta et al 2007) has questioned the need for islet progenitor cells under normal physiological conditions .…”

Section: Survival and Regeneration Of β Cellsmentioning

confidence: 99%

Pancreatic transcription factors and their role in the birth, life and survival of the pancreatic β cell

Bernardo¹,

Hay²,

Docherty³

2008

Molecular and Cellular Endocrinology

149

123

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In recent years major progress has been made in understanding the role of transcription factors in the development of the endocrine pancreas in the mouse. Here we describe how a number of these transcription factors play a role in maintaining the differentiated phenotype of the β cell, and in the mechanisms that allow the β cell to adapt to changing metabolic demands that occur throughout life. Amongst these factors, Pdx1 plays a critical role in defining the region of the primitive gut that will form the pancreas, Ngn3 expression drives cells towards an endocrine lineage, and a number of additional proteins including Pdx1, in a second wave of expression, Pax4, NeuroD1/β2, and MafA act as β cell differentiation factors. In the mature β cell Pdx1, MafA, β2, and Nkx2.2 play important roles in regulating expression of insulin and to some extent other genes responsible for maintaining β cell function. We emphasise here that data from gene expression studies in rodents seldom map on to the known structure of the corresponding human promoters. In the adult the β cell is particularly susceptible to autoimmune mediated attack and to the toxic metabolic milieu associated with over-eating, and utilises a number of these transcription factors in its defence. Pdx1 has anti-apoptotic and proliferative activities that help facilitate the maintenance of β cell mass, while Ngn3 may be involved in the recruitment of progenitor cells, and Pax4 (and possibly HNF1α and Hnf4α) in the proliferation of β cells in the adult pancreas. Other transcription factors with a more widespread pattern of expression that play a role in β survival or proliferation include Foxo1, CREB family members, NFAT, FoxM1, Snail and Asc-2.2

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“…Several studies have reported that progenitors reside within the pancreas itself. Possible sources of these progenitors are the pancreatic ductal epithelium, [4][5][6][7][8][9][10][11] acinar tissue, [12][13][14] islets 15,16 and mesenchyme. [17][18][19][20][21][22][23] Studies have indicated that mesenchymal stem cells (MSCs) are multipotent and capable of deriving functional endoderm.…”

mentioning

confidence: 99%

Epithelial cells within the human pancreas do not coexpress mesenchymal antigens: epithelial–mesenchymal transition is an artifact of cell culture

Seeberger

Eshpeter

Rajotte

et al. 2009

Laboratory Investigation

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Pancreatic mesenchymal stem cells (MSCs) may be derived from human b-cells undergoing reversible epithelial-mesenchymal transition (EMT), suggesting that they could be a potential source of new b-cells. In this study we sought to determine the origin of pancreatic MSCs in the nonendocrine pancreas. Double immunofluorescent (IF) staining and flow cytometry were used to assess the cell phenotype of nonendocrine pancreas tissue following islet procurement, during in vitro expansion of MSCs, and after differentiation. IF staining of paraffin-embedded pancreatic biopsy sections was used to assess cell phenotype in vivo. In this study we demonstrated that: (1) pancreatic epithelial cells do not express MSC antigens in vivo; (2) following islet isolation EpCAM-and CK19-positive epithelial cells coexpressed the MSC antigens CD44 (32±8% and 38±10%) and CD29 (85±4% and 64±4%); (3) during in vitro expansion the number of single-positive epithelial and double-positive epithelial/MSCs decreased whereas the number of single-positive MSCs increased and (4) differentiated MSCs do not revert to a true epithelial cell phenotype in our culture conditions, as epithelial cell surface markers (EpCAM, CK19 and E-Cadherin) are not reexpressed, although the MSC phenotype is altered. This study demonstrates that MSCs may be derived in vitro via a pancreatic epithelial cell undergoing EMT, however it is more likely that a small percentage of MSCs that reside in the adult pancreas are proliferating whereas the epithelial cells are negatively selected by the experimental culture conditions.

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Evidence for the presence of stem cell-like progenitor cells in human adult pancreas

Cited by 47 publications

References 37 publications

Pluripotency-associated stem cell marker expression in proliferative cell cultures derived from adult human pancreas

Pluripotency-associated stem cell marker expression in proliferative cell cultures derived from adult human pancreas

Pancreatic transcription factors and their role in the birth, life and survival of the pancreatic β cell

Epithelial cells within the human pancreas do not coexpress mesenchymal antigens: epithelial–mesenchymal transition is an artifact of cell culture

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