In vitro generation of human pluripotent stem cell derived lung organoids

Dye, Briana R.; Hill, David R.; Ferguson, Michael A H; Tsai, Yu-Hwai; Nagy, Melinda S.; Dyal, Rachel; Wells, James M.; Mayhew, Christopher N.; Nattiv, Roy; Klein, Ophir D.; White, Eric S.; Deutsch, Gail H.; Spence, Jason R.

doi:10.7554/elife.05098

Cited by 671 publications

(695 citation statements)

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“…The development of this model leverages a recently reported method for expanding primary human mammary tissues in culture by using 3D hydrogel scaffolds (18). Because comparable methods have recently been reported for other human tissue types (26,27), we are hopeful that the strategy used here will prove broadly useful for modeling in situ tumors arising within the relevant human tissue microenvironment.…”

Section: Discussionmentioning

confidence: 99%

SMARCE1 is required for the invasive progression of in situ cancers

Sokol

Feng

Jin

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Advances in mammography have sparked an exponential increase in the detection of early-stage breast lesions, most commonly ductal carcinoma in situ (DCIS). More than 50% of DCIS lesions are benign and will remain indolent, never progressing to invasive cancers. However, the factors that promote DCIS invasion remain poorly understood. Here, we show that SMARCE1 is required for the invasive progression of DCIS and other early-stage tumors. We show that SMARCE1 drives invasion by regulating the expression of secreted proteases that degrade basement membrane, an ECM barrier surrounding all epithelial tissues. In functional studies, SMARCE1 promotes invasion of in situ cancers growing within primary human mammary tissues and is also required for metastasis in vivo. Mechanistically, SMARCE1 drives invasion by forming a SWI/SNF-independent complex with the transcription factor ILF3. In patients diagnosed with early-stage cancers, SMARCE1 expression is a strong predictor of eventual relapse and metastasis. Collectively, these findings establish SMARCE1 as a key driver of invasive progression in early-stage tumors.T he past two decades have brought an exponential increase in the diagnosis of early-stage breast lesions, most commonly ductal carcinoma in situ (DCIS). DCIS remains encapsulated within the ductal-lobular architecture of mammary epithelium; in contrast, invasive breast cancers have escaped this architecture by breaking through the basement membrane, a layer of ECM rich in collagen (IV) and laminins that separates epithelial tissues from the adjacent stromal microenvironment ( Fig. S1A) (1). This distinction has a critical impact on patient prognosis: whereas women with DCIS show no reduction in survival 5 y after diagnosis, those with invasive cancers have a 15-74% reduction in 5-y survival rates depending on the extent of tumor invasion at diagnosis (2). Given these observations, there is significant interest in finding genes that promote the invasive progression of early-stage tumors (3). Previous studies have sought molecular alterations present in invasive tumors but not DCIS, leading to the identification of hundreds of genomic and gene-expression alterations specifically associated with invasive cancers (4-6). However, it is unclear if genes that are amplified or up-regulated in invasive cancers also functionally drive DCIS invasion. In large part, the difficulty in addressing this question can be traced to a paucity of experimental systems that model cancer invasion within a microenvironment that faithfully replicates human breast tissue.The treatment of early-stage cancers remains an unresolved issue. Women with early-stage breast cancers-which include DCIS and stage I tumors that have not entered the lymph nodesare typically treated by lumpectomy followed by localized radiation. However, recurrence with metastasis occurs in a significant fraction of women with stage I cancers; if such tumors could be prospectively identified, it would be possible to preemptively adopt a more aggressive therapy. Conver...

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Section: Discussionmentioning

confidence: 99%

SMARCE1 is required for the invasive progression of in situ cancers

Sokol

Feng

Jin

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition, this stably maintained memory may represent chromosomal locations resistant to reprogramming and candidates for disease states of donor cells. As protocols to convert iPSCs to proximal and distal lung cell types are developed [36][37][38] , these NEC-iPSCs may have an advantage in modeling airway diseases such as asthma, COPD, cystic fibrosis, and many others and in studying environmental effects on lung development and homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…This field is rapidly evolving to find more efficient and complete ways to convert primary cells to iPSCs, and to subsequently differentiate iPSCs into specific cell and tissue types of interest. However, differentiation protocols for tissues important for airway disease, such as the lung epithelium, are still being worked out [36][37][38] .…”

Section: Discussionmentioning

confidence: 99%

Cultivate Primary Nasal Epithelial Cells from Children and Reprogram into Induced Pluripotent Stem Cells

Ulm

Mayhew

Debley

et al. 2016

JoVE

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Nasal epithelial cells (NECs) are the part of the airways that respond to air pollutants and are the first cells infected with respiratory viruses. They are also involved in many airway diseases through their innate immune response and interaction with immune and airway stromal cells. NECs are of particular interest for studies in children due to their accessibility during clinical visits. Human induced pluripotent stem cells (iPSCs) have been generated from multiple cell types and are a powerful tool for modeling human development and disease, as well as for their potential applications in regenerative medicine. This is the first protocol to lay out methods for successful generation of iPSCs from NECs derived from pediatric participants for research purposes. It describes how to obtain nasal epithelial cells from children, how to generate primary NEC cultures from these samples, and how to reprogram primary NECs into well-characterized iPSCs. Nasal mucosa samples are useful in epidemiological studies related to the effects of air pollution in children, and provide an important tool for studying airway disease. Primary nasal cells and iPSCs derived from them can be a tool for providing unlimited material for patient-specific research in diverse areas of airway epithelial biology, including asthma and COPD research. Video LinkThe video component of this article can be found at

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“…The virus preferentially infected and replicated in neural progenitors, induced cell death and decreased proliferation, leading to reduced neuronal cell layers and thus phenocopying the microencephaly caused by the virus in human fetuses (Dang et al, 2016;Garcez et al, 2016;Tang et al, 2016). Other organoids such as lung (Dye et al, 2015;Huang et al, 2013), liver Takebe et al, 2013), kidney (Takasato et al, 2015) and fallopian tube organoids (Kessler et al, 2015) may represent ideal models for infections of the respective tissues, such as respiratory virus, malaria parasite, biofilm-producing E. coli or Chlamydia infection, respectively. Future studies will use the unique features of organoids, such as the presence of specific cell types, to better understand infectious and inflammatory diseases.…”

Section: Concluding Remarks and Outlookmentioning

confidence: 99%