Directed differentiation of embryonic stem cells into bladder tissue

Oottamasathien, Siam; Wang, Yong Qing; Williams, Karin; Franco, Omar E.; Wills, Marcia L.; Thomas, John C.; Saba, Katrina; Sharif-Afshar, Ali-Reza; Makari, John H.; Bhowmick, Neil A.; DeMarco, Romano T.; Hipkens, Susan B.; Magnuson, Mark A.; Brock, John W.; Hayward, Simon W.; Pope, John C.; Matusik, Robert J.

doi:10.1016/j.ydbio.2007.01.010

Cited by 93 publications

(66 citation statements)

References 26 publications

(39 reference statements)

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“…Advances in isolation and characterization of tissue-specific SCs will allow further investigation of their differentiation potential and how they are influenced by stromal microenvironments. Our data imply that mammary SCs show a more limited range of differentiation capacity compared with SSCs and ESCs, since under the same experimental conditions, reported by us and others [35], mammary epithelial SCs were unable to fully transform into a prostatic phenotype but instead maintained several of its original differentiation markers, in addition to expressing new ones. In tissue recombinants of other tissue types (including skin, bladder, or esophagus), we showed focal areas of new phenotype (induced by stroma) adjacent to regions of original differentiation markers.…”

Section: Discussionsupporting

confidence: 82%

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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Section: Discussionsupporting

confidence: 82%

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

et al. 2009

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“…This is the first report of FOXA1 and IRF-1 localisation in human urothelium, although FOXA1 expression has been demonstrated previously in bladder, prostate and other epithelial tissues in the adult rat, and is expressed throughout the urothelium of the renal pelvis in adult mice 21 and in the developing mouse lung and bladder. [21][22][23] FOXA1 has been proposed to play an important role in the embryonic development and differentiation primarily of endodermally derived tissues, 21,24,25 including urothelium, 44 although there is evidence that FOXA1 and FOXA2 are required for mesoderm formation. 23 Our study showed FOXA1 expression in urothelia from both endodermally derived bladder and mesodermally derived ureter, implying a mutual differentiation process.…”

Section: Discussionmentioning

confidence: 99%

FOXA1 and IRF-1 intermediary transcriptional regulators of PPARγ-induced urothelial cytodifferentiation

et al. 2008

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The peroxisome proliferator-activated receptor c (PPARc) is a ligand-activated transcription factor that has been implicated in the induction of differentiation of various cell types, including human uroepithelial cells. PPARc-mediated differentiation of normal human urothelial (NHU) cells in vitro requires coinhibition of epidermal growth factor receptor (EGFR) signalling and is characterised by de novo expression of late/terminal differentiation-associated genes, including uroplakins (UPK), over a 6-day period. We used gene microarrays to identify intermediary transcription factors induced in direct response to PPARc activation of EGFR-inhibited NHU cells. FOXA1 and IRF-1 contained consensus cognate binding sites in UPK1a, UPK2, and UPK3a promoters and transcripts were induced within 12 h of PPARc activation; transcription complex formation was confirmed by electromobility shift assays. In urothelium in situ, both FOXA1 and IRF-1 were nuclear and expressed in a differentiationassociated pattern. Knockdown by transient siRNA of either FOXA1 or IRF-1 abrogated PPARc-induced uroplakin expression in vitro. This is the first evidence that ligand activation of PPARc induces expression of intermediary transcription factors that mediate an epithelial differentiation programme and represents a new paradigm for understanding differentiation, regenerative repair and inflammation in epithelial tissues.

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“…Embryonic stem cell-derived endoderm progenitors offer a remarkable potential for the treatment of major diseases affecting the pancreas, liver, lungs, bladder, and prostate [1,2]. Endoderm progenitors would also be useful for the study of congenital diseases [3], gene discovery, toxicology screening, and drug development [4].…”

Section: Introductionmentioning

confidence: 99%

Activin Alters the Kinetics of Endoderm Induction in Embryonic Stem Cells Cultured on Collagen Gels

et al. 2007

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Embryonic stem cell-derived endoderm is critical for the development of cellular therapies for the treatment of disease such as diabetes, liver cirrhosis, or pulmonary emphysema. Here, we describe a novel approach to induce endoderm from mouse embryonic stem (mES) cells using fibronectin-coated collagen gels. This technique results in a homogeneous endoderm-like cell population, demonstrating endoderm-specific gene and protein expression, which remains committed following in vivo transplantation. In this system, activin, normally an endoderm inducer, caused an 80% decrease in the Foxa2-positive endoderm fraction, whereas follistatin increased the Foxa2-positive endoderm fraction to 78%. Our work suggests that activin delays the induction of endoderm through its transient precursors, the epiblast and mesendoderm. Long-term differentiation displays a twofold reduction in hepatic gene expression and threefold reduction in hepatic protein expression of activintreated cells compared with follistatin-treated cells. Moreover, subcutaneous transplantation of activin-treated cells in a syngeneic mouse generated a heterogeneous teratoma-like mass, suggesting that these were a more primitive population. In contrast, follistatin-treated cells resulted in an encapsulated epithelial-like mass, suggesting that these cells remained committed to the endoderm lineage. In conclusion, we demonstrate a novel technique to induce the direct differentiation of endoderm from mES cells without cell sorting. In addition, our work suggests a new role for activin in induction of the precursors to endoderm and a new endoderm-enrichment technique using follistatin. STEM CELLS 2008;26:474 -484 Disclosure of potential conflicts of interest is found at the end of this article.

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Directed differentiation of embryonic stem cells into bladder tissue

Cited by 93 publications

References 26 publications

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

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

FOXA1 and IRF-1 intermediary transcriptional regulators of PPARγ-induced urothelial cytodifferentiation

Activin Alters the Kinetics of Endoderm Induction in Embryonic Stem Cells Cultured on Collagen Gels

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