In vivo reprogramming of adult pancreatic exocrine cells to β-cells

Zhou, Qiao; Brown, Juliana; Kanarek, Andrew; Rajagopal, Jayaraj; Melton, Douglas A.

doi:10.1038/nature07314

Cited by 1,865 publications

(1,597 citation statements)

References 41 publications

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“…Although it will likely be difficult to apply such methods in humans, we propose that such manipulations will inform as to the mechanisms of plasticity and the epigenomic alterations that need to be induced as facilitatory or directly instructive on cell fate. One landmark in reinvigorating such research comes from the finding that acinar cells could convert into b-cells in vivo when given an adenovirus-borne cocktail of three transcription factors (Ngn3, Pdx1, and MafA) (Zhou et al, 2008) (Fig. 5).…”

Section: Genetic Manipulation-based Reprogrammingmentioning

confidence: 99%

Pancreas organogenesis: From bud to plexus to gland

Pan

Wright

2011

Developmental Dynamics

524

594

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Pancreas oganogenesis comprises a coordinated and highly complex interplay of signaling events and transcriptional networks that guide a step-wise process of organ development from early bud specification all the way to the final mature organ state. Extensive research on pancreas development over the last few years, largely driven by a translational potential for pancreatic diseases (diabetes, pancreatic cancer, and so on), is markedly advancing our knowledge of these processes. It is a tenable goal that we will one day have a clear, complete picture of the transcriptional and signaling codes that control the entire organogenetic process, allowing us to apply this knowledge in a therapeutic context, by generating replacement cells in vitro, or perhaps one day to the whole organ in vivo. This review summarizes findings in the past 5 years that we feel are amongst the most significant in contributing to the deeper understanding of pancreas development. Rather than try to cover all aspects comprehensively, we have chosen to highlight interesting new concepts, and to discuss provocatively some of the more controversial findings or proposals. At the end of the review, we include a perspective section on how the whole pancreas differentiation process might be able to be unwound in a regulated fashion, or redirected, and suggest linkages to the possible reprogramming of other pancreatic cell-types in vivo, and to the optimization of the forward-directed-differentiation of human embryonic stem cells (hESC), or induced pluripotential cells (iPSC), towards mature b-cells. Developmental Dynamics 240:530-565,

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Section: Genetic Manipulation-based Reprogrammingmentioning

confidence: 99%

Pancreas organogenesis: From bud to plexus to gland

Pan

Wright

2011

Developmental Dynamics

524

594

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“…This is clear in iPS studies, where Oct4, Klf4 and Sox2 are critical to the maintenance of ES cell pluripotency [103], but also applies in other contexts, such as the reprogramming of exocrine cells to β cells in the pancreas, and the progressive reprogramming of B cells into macrophages, and later, into iPS cells [90,91,93]. Pdx1, used in the in vivo pancreas reprogramming and the liver to pancreas cell reprogramming, is critical for pancreas development and islet β cell specification [104,105].…”

Section: Nuclear Reprogrammingmentioning

confidence: 99%

“…Forced transdifferentiation of one cell type into another also requires cellular reprogramming. Most recently, Zhou et al [93] have shown that adult pancreatic exocrine cells can be directly reprogrammed in vivo to insulinsecreting β cells capable of ameliorating hyperglycaemia in a streptozotocin-and fasting-induced mouse model of diabetes. Adult liver cells can also be reprogrammed to take on pancreatic islet β cell characteristics and are also capable of producing insulin and ameliorating hypoglycaemia in diabetic mice [94,95].…”

Section: Nuclear Reprogrammingmentioning

confidence: 99%

Stem cell options for kidney disease

Hopkins

Rae

et al. 2008

The Journal of Pathology

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Chronic kidney disease (CKD) is increasing at the rate of 6-8% per annum in the US alone. At present, dialysis and transplantation remain the only treatment options. However, there is hope that stem cells and regenerative medicine may provide additional regenerative options for kidney disease. Such new treatments might involve induction of repair using endogenous or exogenous stem cells or the reprogramming of the organ to reinitiate development. This review addresses the current state of understanding with respect to the ability of non-renal stem cell sources to influence renal repair, the existence of endogenous renal stem cells and the biology of normal renal repair in response to damage. Understanding repair options via an understanding of renal developmentThe prevalence and incidence of chronic kidney disease (CKD) is increasing at 6-8% per annum in the USA alone, largely as a result of increased prevalence of diabetes and obesity [1]. To understand what might be possible with respect to cellular therapies or regenerative medicine for the kidney, one first needs to consider what is understood about normal renal development and response to injury. The kidney has been classically regarded as an organ with minimal cellular turnover and no capacity for regeneration. The subsequent identification of stem cells in a number of such organs, including the brain, has challenged this view. However, the dogma remains that the kidney reaches a maximal complement of nephrons and then loses these over time [2]. This dogma is drawn from our understanding of the development of this organ. The progenitor population during developmentThe kidney is mesodermal in origin and develops from two populations derived from intermediate mesoderm, the ureteric bud (UB) and the metanephric mesenchyme (MM). While an even broader potential had been proposed [3], genetic and lineage analyses have confirmed that the MM gives rise to all portions of the nephron other than the collecting ducts and also gives rise to elements of the renal interstitium [4][5][6]. The UB gives rise to the ureter and collecting ducts only. The MM is apparently not homogeneous but forms condensed mesenchyme around the tips of the branching UB. This cap mesenchyme (CM) contains self-renewing progenitors capable of generating all cells of the nephron other than the collecting ducts via an initial mesenchyme-epithelial transition (MET) event throughout the prenatal developmental period [6]. The continued expression of the transcription factor Six2 in CM is required for maintenance of this stem cell population during kidney development [5]. As the UB branches and extends through the MM, individual MET events occur at the underside of each tip to form a new nephron [2]. This nephron endowment therefore proceeds from the centre of the kidney out to the periphery, with the CM stem cell field remaining on the outer edge of the expanding organ. Endowment of new nephrons is restricted to prenatal development in humans, while in rodents it persists only until the imm...

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“…Nevertheless, de-differentiation in committed cells can be induced by somatic cell nuclear transfer and nonoocyte-based approaches such as fusion of somatic cells with embryonic SCs, treatment of somatic cells with extracts of pluripotent cells, and/or retroviral transduction of somatic cells to overexpress pluripotency genes [2]. Therefore, the capability for reprogramming and transdifferentiation is retained into adulthood [3,4]. The potential for transdifferentiation of differentiated somatic (adult) epithelial SCs opens up novel avenues for regenerative medicine and avoids the ethical issues surrounding the use of embryonic SCs, but it is crucial to ensure the safety of this process [1].…”

Section: Introductionmentioning

confidence: 99%

Lineage Enforcement by Inductive Mesenchyme on Adult Epithelial Stem Cells across Developmental Germ Layers

et al. 2009

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During development, cell differentiation is accompanied by the progressive loss of pluripotent gene expression and developmental potential, although de‐differentiation in specialized cells can be induced by reprogramming strategies, indicating that transdifferentiation potential is retained in adult cells. The stromal niche provides differentiating cues to epithelial stem cells (SCs), but current evidence is restricted to tissue types within the same developmental germ layer lineage. Anticipating the use of adult SCs for tissue regeneration, we examined if stroma can enforce lineage commitment across germ layer boundaries and promote transdifferentiation of adult epithelial SCs. Here, we report tissue‐specific mesenchyme instructing epithelial cells from a different germ layer origin to express dual phenotypes. Prostatic stroma induced mammary epithelia (or enriched Lin−CD29HICD24+/MOD mammary SCs) to generate glandular epithelia expressing both prostatic and mammary markers such as steroid hormone receptors and transcription factors including Foxa1, Nkx3.1, and GATA‐3. Array data implicated Hh and Wnt pathways in mediating stromal‐epithelial interactions (validated by increased Cyclin D1 expression). Other recombinants of prostatic mesenchyme and skin epithelia, or preputial gland mesenchyme and bladder or esophageal epithelia, showed foci expressing new markers adjacent to the original epithelial differentiation (e.g., sebaceous cells within bladder urothelium), confirming altered lineage specification induced by stroma and evidence of cross‐germ layer transdifferentiation. Thus, stromal cell niche is critical in maintaining (or redirecting) differentiation in adult epithelia. In order to use adult epithelial SCs in regenerative medicine, we must additionally regulate their intrinsic properties to prevent (or enable) transdifferentiation in specified SC niches. STEM CELLS 2009;27:3032–3042

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In vivo reprogramming of adult pancreatic exocrine cells to β-cells

Cited by 1,865 publications

References 41 publications

Pancreas organogenesis: From bud to plexus to gland

Pancreas organogenesis: From bud to plexus to gland

Stem cell options for kidney disease

Lineage Enforcement by Inductive Mesenchyme on Adult Epithelial Stem Cells across Developmental Germ Layers

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