Intestinal Stem Cells: Dynamics and Regulation. Vincent W. Yang, MD, PhD, Department of Medicine, Stony Brook University, Stony Brook, NY 11794, U.S.A.

The mammalian intestinal epithelium is a continuously renewing and highly regenerative tissue in which numerous biological processes such as proliferation, differentiation, migration, and apoptosis are carefully choreographed to achieve homeostasis. Studies have indicated that numerous signaling pathways includingWNT, NOTCH, BMP and HH form important components of the regulatory network and converge upon the intestinal crypts where intestinal stem cells (ISCs) reside. Recent studies have identified distinct populations of ISCs based on the markers that they express. At the present time ISCs are broadly divided into two broad functional groups: active ISCs (aISCs), a population of crypt base columnar (CBC) cells expressing LGR5, function as the multipotent stem cells during homeostasis, and quiescent or reserve ISCs (qISCs or rISCs), which express various markers such as BMI1, LRIG1, mTERT, HOPX,and DCLK1, are slow-cycling during homeostasis but serve as a source of regeneration following depletion of aISCs due to injury. Despite these advances significant gaps remain with regard to how extracellular milieu influence behavior of ISCs and how plasticity of ISCs at physiologic and pathophysiological states is mediated intracellularly.

Krüppel-like factors (KLFs) are a family of zinc finger-containing transcription factors that exert important roles in regulating diverse physiological and pathophysiological processes. Two members in particular, KLF4 and KLF5, have been shown to be essential for the maintenance of intestinal epithelial cell (IEC) homeostasis. While KLF4 is normally expressed in post-mitotic or quiescent IECs, KLF5 is expressed in proliferating crypt epithelial cells. Intestine-specific deletion of either factor in transgenic mice results in altered intestinal epithelial homeostasis. Here we show that KLF4 is expressed in BMI1-expressing qISCs and KLF5 in LGR5-expressing aISCs. Upon injury from  irradiation which ablates aISCs, BMI1-qISCs become activated and serve as a source of regeneration of the epithelium. Importantly both KLF4 and KLF5 are critical for the ability of BMI1-expressing ISCs to servein the regenerating response. Given the fact that expression of both KLFs have been shown to be perturbed under pathological conditions such as cancer, infection and DNA damage, knowledge derived from these studies has potential therapeutic implications in diseases of the gastrointestinal tract.

References:

  • Nandan, M. O., Ghaleb, A.M., Liu, Y., Bialkowska, A.B., McConnell, B.B., Shroyer, K., Robine, S., and Yang, V.W. (2014) Inducible intestine-specific deletion of Krüppel-like factor 5 is characterized by a regenerative response in adult mouse colon. Developmental Biology 387, 191-202.
  • Nandan, M.O., Ghaleb, A.M., Bialkowska, A.B., and Yang, V.W. (2015) Krüppel-like factor 5 is essential for proliferation and survival of mouse intestinal epithelial stem cells. Stem Cell Research 14, 10-19.
  • Talmasov, D., Zhang, X., Yu, B., Nandan, M.O., Bialkowska, A.B., Elkarim, E., Kuruvilla, J., Yang, V.W., and Ghaleb, A.M. (2015) Krüppel-like factor 4 is a radioprotective factor for the intestine following -radiation-induced gut injury in mice. American Journal of Physiology – Gastrointestinal and Liver Physiology 308, G121-138.
  • Kuruvilla, J.G., Kim, C.K., Ghaleb, A.M., Bialkowska, A.B., Kuo, C.J., and Yang, V.W. (2016) Krüppel-like factor 4 modulates development of BMI1+ intestinal stem cell-derived lineage following  radiation-induced gut injury in mice. Stem Cell Reports 6, 815-824.