Chengcheng (Alec) Zhang, Ph.D.
Ph.D, University of Illinois at Urbana-Champaign - 1999
Assistant Professor, Departments of Physiology, and Developmental Biology
Michael L. Rosenberg Scholar in Biomedical Research, UT Southwestern Medical Center
Office: (214) 645-6320
FAX: (214) 648-1960
Building ND, Room 5.136E
E-mail: Alec.Zhang@UTSouthwestern.edu
The long-term goal of our laboratory is to gain a comprehensive understanding of the molecular mechanisms that govern the adult stem cell fate determination, and to apply the knowledge obtained from these studies to the development of new stem cell transplantation strategies and gene therapies for treating cancer and other diseases. Our study is focused on hematopoietic stem cells (HSCs).
HSCs are defined by their ability to self-renew and to differentiate into all blood cell types. These very rare cells form the basis of bone marrow transplantation for treatment of leukemia and other cancers, and are also a promising cell target for developing gene therapies for treating a broad variety of human diseases. However, development of these important clinical applications of HSCs is severely hampered by the lack of understanding of the extracellular and intracellular signals that govern their fates and the difficulty in ex vivo expansion of these cells.
Recently we identified several groups of novel growth factors for HSCs, including Angiopoietin-like proteins (Angptls). We subsequently developed a very potent but simple serum-free culture system, which is capable of stimulating a 24-30 fold expansion of long-term HSCs. This provides a great system to study the control of cell fates of HSCs: self-renewal, differentiation, apoptosis, and mobilization, and may provide us the opportunity to uncover the mystery of “stemness” of adult stem cells. We therefore seek to study:
1. mechanisms by which Angiopoietin-like proteins regulate HSC expansion, and the interaction of HSCs and their in vivo microenvironment. No member of the angiopoietin-like protein family (Angptls) has previously been suggested to act on hematopoiesis or stem cells, and their receptors and signal transduction pathways are unknown. Our study suggests that the effects of Angptls on HSC expansion are additive to those of other known HSC factors and they may activate new signaling pathways in HSCs. Therefore, it is very important to study the mechanisms by which Angptls stimulate expansion of HSCs. The principal hypothesis underlying this study is that Angptls interact with currently unknown receptors on the surface of HSCs. This results in activation of specific intracellular signaling pathways and induction of transcription of target genes that are required for self-renewal or survival of HSCs. To this end, we will use expression cloning and other methods to isolate receptors for Angptls. In parallel, we will dissect the specific intracellular signal transduction pathways induced by Angptls, and assess the genes transcriptionally activated upon treatment with Angptls. Furthermore, the study of the in vivo physiological function of Angiopoietin-like proteins will reveal the details of the regulation of the cell fate determination of HSCs by their microenvironment.
2. ex vivo expansion of HSCs for cell therapy and gene therapy. The ultimate goal of our study of the ex vivo expansion of HSCs is to apply the gained knowledge to human patients. Further optimization of ex vivo expansion of HSCs will be carried out by comparing the effects of different combinations of known and novel growth factors. To use our potent HSC culture system as a platform for gene therapy, we will introduce a functional wild-type gene into mutant HSCs isolated from a disease model mice, followed by ex vivo expansion and selection of the positively infected HSCs, and infuse them into the mutant recipients to correct the disease.
3. the interplay between HSCs and cancer.
We believe research in these directions will greatly enhance our understanding of the molecular mechanisms that control stem cells and cancer, and potentially contribute to development of new strategies of stem cell engineering, transplantation, and gene therapy.
Awards & Honors:
Howard Temin KO1 award, National Cancer Institute (2006)
Endowed Scholar, UT Southwestern MedicalCenter (2006)
Selected References:
Zhang CC, Krieg S, and Shapiro DJ. 1999. HMG-1 Stimulates Estrogen Response Element Binding by Estrogen Receptor from Stably Expressed HeLa Cells. Molecular Endocrinology 13: 632-643.
Zhang CC and Shapiro DJ. 2000. Activation of the p38 Mitogen-activated Protein Kinase Pathway by Estrogen or by 4-Hydroxy Tamoxifen is Coupled to Estrogen Receptor-induced Apoptosis. Journal of Biological Chemistry 275: 479-486.
Zhang CC, Glenn K, Kuntz M, and Shapiro DJ. 2000. High Level Expression of Full-length Estrogen Receptor in E.coli is Facilitated by the Uncoupler of Oxidative Phosphorylation, CCCP. Journal of Steroid Biochemistry and Molecular Biology 74: 169-178.
Tomas E, Tsao TS, Saha AK, Murrey HE, Zhang CC, Itani SI, Lodish HF, Ruderman NB. 2002. Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Proc Natl Acad Sci U S A 99:16309-16313.
Zhang CC and Lodish HF. 2004. Insulin-like growth factor 2 expressed in a novel fetal liver cell population is a growth factor for hematopoietic stem cells. Blood 103: 2513-2521. Epub 2003 Oct 30.
Zhang CC and Lodish HF. 2005. Murine hematopoietic stem cells change their surface phenotype during ex vivo expansion. Blood 105: 4314-4320. Epub 2005 Feb 8.
Thomas M, Lu JJ, Ge Q, Zhang CC, Chen J, Klibanov AM. 2005. Full deacylation of polyethylenimine dramatically boosts its gene delivery efficiency and specificity to mouse lung. Proc Natl Acad Sci U S A Epub 2005 Apr 11.
Zhang CC, Kaba M, Ge G, Xie K, Tong W, Hug C, Lodish HF. 2006. Angiopoietin-like proteins stimulate ex vivo expansion of hematopoietic stem cells. Nature Medicine 12: 240-245.
Zhang CC, Steele AD, Lindquist S, Lodish HF. 2006. Prion protein is expressed on long-term repopulating hematopoietic stem cells and is important for their self-renewal. Proc Natl Acad Sci U S A. 103: 2184-2189.
