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Telomerase-immortalized human mammary stem/progenitor cells with ability to self-renew and differentiate.

ABSTRACT: There is increasing evidence that breast and other cancers originate from and are maintained by a small fraction of stem/progenitor cells with self-renewal properties. Whether such cancer stem/progenitor cells originate from normal stem cells based on initiation of a de novo stem cell program, by reprogramming of a more differentiated cell type by oncogenic insults, or both remains unresolved. A major hurdle in addressing these issues is lack of immortal human stem/progenitor cells that can be deliberately manipulated in vitro. We present evidence that normal and human telomerase reverse transcriptase (hTERT)-immortalized human mammary epithelial cells (hMECs) isolated and maintained in Dana-Farber Cancer Institute 1 (DFCI-1) medium retain a fraction with progenitor cell properties. These cells coexpress basal (K5, K14, and vimentin), luminal (E-cadherin, K8, K18, or K19), and stem/progenitor (CD49f, CD29, CD44, and p63) cell markers. Clonal derivatives of progenitors coexpressing these markers fall into two distinct types--a K5(+)/K19(-) type and a K5(+)/K19(+) type. We show that both types of progenitor cells have self-renewal and differentiation ability. Microarray analyses confirmed the differential expression of components of stem/progenitor-associated pathways, such as Notch, Wnt, Hedgehog, and LIF, in progenitor cells compared with differentiated cells. Given the emerging evidence that stem/progenitor cells serve as precursors for cancers, these cellular reagents represent a timely and invaluable resource to explore unresolved questions related to stem/progenitor origin of breast cancer.

SUBMITTER: Zhao X

PROVIDER: S-EPMC2922525 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Telomerase-immortalized human mammary stem/progenitor cells with ability to self-renew and differentiate.

Zhao Xiangshan X Malhotra Gautam K GK Lele Subodh M SM Lele Manjiri S MS West William W WW Eudy James D JD Band Hamid H Band Vimla V

Proceedings of the National Academy of Sciences of the United States of America 20100726 32

There is increasing evidence that breast and other cancers originate from and are maintained by a small fraction of stem/progenitor cells with self-renewal properties. Whether such cancer stem/progenitor cells originate from normal stem cells based on initiation of a de novo stem cell program, by reprogramming of a more differentiated cell type by oncogenic insults, or both remains unresolved. A major hurdle in addressing these issues is lack of immortal human stem/progenitor cells that can be d ...[more]

PMID: 20660721

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Project description:Immortalized colonic epithelial progenitor cells derived from normal human colon biopsies express stem cell markers and differentiate in vitro The sustained growth of normal non-transformed human colonic epithelial cells has historically been exceptionally challenging. We here report the successful long-term propagation of colon biopsy derived cells expressing both epithelial and mesenchymal features, intestinal stem cell markers, and demonstrating multilineage epithelial differentiation capability. Cells isolated from the biopsies of two patients undergoing routine screening colonoscopy have been successfully passaged in vitro, subsequently immortalized with non-oncogenic proteins (cyclin dependent kinase 4 [CDK4] and the catalytic component of human telomerase [hTERT]), and maintained for well over a year in continuous cell culture. Immunofluorescence experiments reveal the immortalized populations of cells significantly express the progenitor epithelial cell marker mucin-1 and the colon epithelial specific marker A33. In addition, staining shows subsets of cells express chromogranin A, mucin-2, and dipeptyl peptidase 4, corresponding to neuroendocrine, mucus secreting, and absorptive colonic cell lineages, respectively. The cells also possess some mesenchymal features, including vimentin and α- smooth muscle actin expression when proliferating actively. Finally, immortalized cells express various stem cell markers including LGR5, BMI1, CD29, and CD44. When cells are seeded at low density in Matrigel® in the absence of a mesenchymal feeder layer individual cells are able to divide and form self-organizing, cyst-like structures with a subset of cells exhibiting either mucin-2 or polarized villin staining. These findings demonstrate that the immortalized human colonic cells are capable of self renewal and multilineage differentiation. These cells should serve as valuable cellular reagents for studying normal colon stem cell biology, differentiation, and disease development.

Dataset Information

Telomerase-immortalized human mammary stem/progenitor cells with ability to self-renew and differentiate.

Publications

Telomerase-immortalized human mammary stem/progenitor cells with ability to self-renew and differentiate.

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