Abstract
Autologous transplantation of human epidermal stem cells cultured in Green’s method is one of the first examples of utilizing adult stem cells in regenerative medicine. Using the same method, we cloned p63-expressing distal airway stem cells and showed their essential role in lung regeneration in a mouse model of acute respiratory distress syndrome. However, adult stem cells of columnar epithelial tissues had until recently evaded all attempts at cloning. To address this issue, we developed a novel technology that enabled cloning ground-state stem cells of the columnar epithelium. The adaption of this technology to clone stem cells of cancer precursors furthered our understanding of the dynamics of processes such as clonal evolution and dominance in Barrett’s esophagus, as well as for testing platforms for chemical screening. Taken together, the properties of these ground-state stem cells, including unlimited propagation, genomic stability, and regio-specificity, make them ideal for regenerative medicine, disease modeling and drug discovery.
Highlights
One of the most exciting directions in medicine is based on stem cell research, which holds the promise of treatments and cures for various diseases and conditions that have so far frustrated traditional pharmaceutical approaches
Both stem cell research and clinical trials in regenerative medicine are presently dominated by pluripotent stem cells: embryonic stem cells (ESC) and induced pluripotent stem cells
In addition to the growth factors such as IGF and EGF that were included in the medium in Green’s method, the Xian–McKeon lab developed a media containing novel combinations of growth factors and regulators of TGF-β, Wnt/β-catenin, EGF, IGF, and Notch pathways [25,26] that supports the maintenance of human columnar epithelial stem cells, including intestinal stem cells, in a highly clonogenic, ground-state form
Summary
One of the most exciting directions in medicine is based on stem cell research, which holds the promise of treatments and cures for various diseases and conditions that have so far frustrated traditional pharmaceutical approaches. Many researchers maintain these columnar epithelia as regenerative “organoids” that contain a minor fraction of stem cells that drive their growth [11,12,13] While their potential for regenerative medicine is obvious [14], organoids are labor-intensive, very slow to expand and mostly comprised of differentiated cells rather than regenerative stem cells. To overcome this significant barrier in adult stem cell biology, highly robust technologies have been developed to clone and propagate clonogenic, “ground-state” stem cells of the human intestine and colon [15]. These cultured stem cells show remarkable stability in their genomic integrity and epigenetic commitment programs, show unlimited replicative expansion and maintain high clonogenicity, suggesting tremendous potential in disease modeling and regenerative medicine
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