Research Area

stem cell biology, developmental biology, degenerative eye diseases, stem cell therapy

Profile

Dr. Ting Xie has moved to HKUST to serve as the head and chair professor of Division of Life Science since the beginning of 2021. He obtained his Bachelor’s and Master’s degrees on plant genetics and breeding from China Agricultural University, and his Ph.D. degree on molecular biology and biochemistry from Rutgers University. He did his postdoctoral training in the Allan Spradling’s laboratory at Carnegie Institution of Science as a Howard Hughes Medical Institute postdoctoral fellow. Then, he joined the Stowers Institute to run his independent lab for 20 years. Before he moved to HKUST, he was a full investigator at Stowers Institute and also a professor in University of Kansas Medical Center. His main research interest is stem cell biology and tissue regeneration. He is one of the leaders and pioneers in studying the stem cell niche and its mechanisms controlling self-renewal. Dr. Xie was among the first to experimentally demonstrate the existence of the stem cell niche. His laboratory has also proposed and demonstrated the existence of the differentiation niche for controlling stem cell lineage specification. His laboratory has also elucidated how the two niches work together to control stem cell development and thus tissue regeneration. Recently, he has expanded his research interest to retinal degenerative diseases and developing new treatment strategies. So far, Dr. Xie has published over 70 articles in high-profile journals, including Science, Nature and Cell.  He received Hudson Award in 2003, and has been serving on the scientific advisory board of The Glaucoma Foundation and on the editorial board of Cell Research, Development and eight other scientific journals.

Research Summary

In past two decades, the Xie lab has been using germline stem cells (GSCs) in the Drosophila ovary as a model to investigate how two niches work with intrinsic factors to control stem cell self-renewal, differentiation, competition and aging. In recent years, the Xie lab has been using the mouse eye as a model to explore the causes of human retinal degenerative diseases and the potential of stem cell therapy in treating those diseases. Here are research accomplishments and future directions:

1. Niche and intrinsic control of stem cell self-renewal
   Dr. Xie has demonstrated that GSC self-renewal is controlled by the niche composed of cap cells (Science, 2000). The Xie lab has further shown that that anterior inner germarial sheath (IGS) cells are also the part of the GSC niche for promoting self-renewal by producing Netrin A (PLoS Genet, 2011; Curr Biol, 2021). His lab has further elucidated that; 1) Dpp/BMP is a key niche signal functioning in short range to control GSC self-renewal and aging by directly repressing differentiation; 2) E-cadherin anchors stem cells in the niche, and is also directly linked to stem cell competition and quality control; 3) Notch signaling directly controls niche formation and size (Cell, 1998; Development, 2003, 2007; Science, 2002; PNAS, 2002; Cell Stem Cell, 2007, 2008). These findings have provided important insight into niche structure, function and formation.The Xie lab has identified various classes of intrinsic factors controlling GSC self-renewal by distinct mechanisms: 1) microtubule-binding protein Lissencephaly-1 (Lis-1) and epigenetic factor ISWI promote both BMP signaling and E-cadherin-mediated cell adhesion (PNAS, 2010; Science, 2005); 2) translation initiation factor eIF4A and CSN4 interacts with Bam to inactivate its function and thus repress differentiation (PNAS, 2009; Nature, 2014); 3) miRNA component Dcr-1, translation regulator Pelota, H3K9 trimethylase Eggless and 5mC RNA binding protein Yps repress Bam-independent differentiation (Development, 2005; Curr Biol, 2007; PLoS Genet, 2011; PNAS, 2020). In addition, DNA damage disrupts GSC self-renewal primarily through Chk2 activation (Cell Reports, 2015; Development, 2015; Developmental Cell, 2017). Therefore, intrinsic factors control GSC self-renewal by strengthening GSC-niche interactions and repressing various differentiation pathways.Many outstanding questions related to GSC self-renewal still remain to be addressed, such as how do different niche-derived factors and various intrinsic factors work cooperatively to control GSC self-renewal and aging? how do niche signals cooperate with intrinsic factors to control self-renewal at the molecular level? The answers to these questions will help gain a better understanding of the molecular control of GSC self-renewal.
2. Niche and intrinsic control of stem cell lineage differentiation
   Because of versatile Drosophila genetics and well-defined GSC lineage, the Xie lab has demonstrated that posterior IGS cells (also known as escort cells) form a differentiation niche for controlling GSC lineage specification (Development, 2011). His lab has further demonstrated the requirement of Hh signaling, Wnt signaling, EGFR signaling, COP9 signalosome, the exocyst complex, Rho1, H3K9 trimethylase Eggless and piRNA component Piwi in the niche and also cross-regulate one another to control GSC progeny differentiation by preventing BMP signaling, maintaining IGS-germ cell interactions or both (Development, 2011, 2015, 2019; PLoS Genet, 2011; eLife, 2015; Science Advances, 2020). Finally, his lab has also shown that the differentiation niche contains three compartments for stepwise control of germ cell cyst formation, meiotic entry and oocyte specification/germline cyst shape change (Curr Biol, 2021). These findings have suggested that GSC progeny differentiation is programmed step-by-step by the niche.The Xie lab has demonstrated that intrinsic factors promote GSC progeny differentiation by repressing the expression or function of self-renewal factors or promoting the expression of other differentiation factors: 1) differentiation factor Bam interacts with Bgcn and eIF4A to form a ternary protein complex to repress translational of self-renewal factors and promote the expression of differentiation factors (PNAS, 2009); 2) Bam can also convert the self-renewal function of the COP9 complex into the differentiation-promoting complex by recruiting away CSN4 via protein competition (Nature, 2014); 3) The CCR4-Not complex, piRNA component Aubergine and 5mC RNA binding protein Yps promote the expression of self-renewal factors and repress the expression of differentiation factors (Cell Reports, 2015; Developmental Cell, 2017; PNAS, 2020). Therefore, these findings have uncovered key niche and intrinsic factors and their acting mechanisms in controlling GSC progeny differentiation.Many outstanding questions related to GSC progeny differentiation are also still not answered, such as how do different niche compartments control stepwise GSC progeny differentiation? how do niche signals work with intrinsic factors to control each differentiation step? how do the two niches work cooperatively to control the balance between self-renewal and differentiation? The answers to these questions will provide new insight into how GSC progeny differentiation is controlled molecularly. The Xie lab is also interested in investigating spermatogonial stem cell niches in the mouse testis in the future.
3. Retinal degenerative diseases and potential therapies
   Stem cells have been advocated to treat various degenerative diseases. In human eyes, two major retinal degenerative diseases, glaucoma and age-related macular degeneration (AMD), cause the loss of retinal ganglion cells (RGCs) and photoceptors, respectively. The Xie lab has used the mouse eye to show that in vitro expanded retinal stem cells (RSCs) can generate functional photoreceptors capable of restoring the light response of the blind rd1 mutant mouse that lacks photoreceptors (Cell Research, 2013). However, the transplanted photoreceptors die again after 3 months, suggesting that the persistent disease condition might be the major roadblock for stem cell therapy. Although the transplanted RSCs can survive and differentiate into RGCs that integrate into the RGC layer, those RGSCs fail to extend their axons to the brain. Therefore, some obstacles must be overcome in order to develop successful stem cell therapies for those eye diseases.For the time being, stopping the progression is still the best strategy for treating retinal degenerative diseases. However, there are no good treatment strategies for stopping them due to their unknown causes. The ciliary body (CB) secrets aqueous humour for maintaining intraocular pressure, which elevation is an important risk factor for glaucoma. the Xie lab has been studying CB development and function to demonstrate that Notch signaling not only promotes CB development but also controls the secretion of aqueous humor and vitreous proteins, which are essential for the survival of various eye tissues, including the cornea, the lens and the retina (PNAS, 2013; Cell Reports, 2021). These findings indicate that the CB creates the intraocular microenvironment or “niche” for supporting various eye tissues, and also potentially holds some secrets for degenerative eye diseases. Currently, the Xie lab is trying to uncover the causes for neuronal degeneration in glaucoma and endothelium degeneration in Fuchs cornea dystrophy by identifying critical CB-secreted factors, and is also interested in further developing gene and stem cell therapies for these degenerative eye diseases.

Representative Publications

Ten publications in the recent 10 years

1. Pang J, Le L, Zhou Y, Renjun Tu, Hou Q, Tsuchiya D, Lewis B, Corbin T, Durnin M, Li H, Ashery-Padan R, Yan D, Xie T. NOTCH signaling controls ciliary body morphogenesis and secretion by directly regulating Nectin protein expression. Cell Rep. 2021 Jan 12;34(2):108603.
2. Tu R, Duan B, Song X, Chen S, Scott A, Hall K, Blanck J, DeGraffenreid D, Li H, Perera A, Haug J, Xie T. Multiple niche compartments orchestrate stepwise germline stem cell progeny differentiation. Curr Biol. 2021 Feb 22; 31(4): 827-839.
3. Tu R, Duan B, Song X, Xie T. Glypican Dlp-mediated Hedgehog and Wnt signaling interdependence is crucial in the niche for germline stem cell progeny differentiation. Sci Adv. 2020; 6(20):eaaz0480.
4. Zou F, Tu R, Duan B, Yang Z, Ping Z, Song X, Chen S, Price A, Li H, Scott A, Perera A, Li S, Xie T. Drosophila YBX1 homolog YPS promotes ovarian germline stem cell development by preferentially recognizing 5-methylcytosine RNAs. Proc Natl Acad Sci U S A. 2020; 117(7): 3603-3609.
5. Ma X, Zhu X, Han Y, Story B, Do T, Song X, Wang S, Zhang Y, Blanchette M, Gogol M, Malanowski K, Peak A, Anoja P, Xie T. Aubergine controls germline stem cell self-renewal and progeny differentiation via distinct mechanisms. Developmental Cell 2017; 41(2):157-169.
6. Wang S, Gao Y, Song X, Ma X, Zhu X, Mao Y, Yang Z, Ni J, Li H, Malanowski KE, Anoja P, Park J, Haug J and Xie T. Wnt signaling-mediated redox regulation maintains the germ line stem cell differentiation niche. eLife. 2015; 4:e08174.
7. Pan L, Wang S, Lu T, Weng C, Song X, Park JK, Sun J, Yang ZH, Yu J, Tang H, McKearin DM, Chamovitz DA, Ni J, Xie T. Protein competition switches the function of COP9 from self-renewal to differentiation. Nature. 2014; 514(7521):233-6.
8. Zhou Y, Tanzie C, Yan Z, Chen S, Duncan M, Gaudenz K, Li H, Seidel C, Lewis B, Moran A, Libby RT, Kiernan AE, Xie T. Notch2 regulates BMP signaling and epithelial morphogenesis in the ciliary body of the mouse eye. Proc Natl Acad Sci U S A. 2013; 110(22):8966-71.
9. Li T, Lewallen M, Chen S, Yu W, Zhang N, Xie T. Multipotent stem cells isolated from the adult mouse retina are capable of producing functional photoreceptor cells. Cell Res. 2013; 23(6):788-802.
10. Kirilly D, Wang S, Xie T. Self-maintained escort cells form a germline stem cell differentiation niche. Development. 2011; 138:5087-5097.

Ten publications in the previous 10 years

1. Chen S, Kaneko S, Ma X, Chen X, Ip YT, Xu L, Xie T. Lissencephaly-1 controls germline stem cell self-renewal through modulating bone morphogenetic protein signaling and niche adhesion. Proc Natl Acad Sci U S A. 2010; 107:19939-19944.
2. Shen R, Weng C, Yu J, Xie T. eIF4A controls germline stem cell self-renewal by directly inhibiting BAM function in the Drosophila ovary. Proc Natl Acad Sci U S A. 2009; 106:11623-11628.
3. Jin Z, Kirilly D, Weng C, Kawase E, Smith S, Schwartz J, Xie T. Differentiation-defective stem cells outcompete normal stem cells for niche occupancy in the Drosophila ovary. Cell Stem Cell. 2008; 2:39-49.
4. Pan L, Chen S, Weng C, Call G, Zhu D, Tang H, Zhang N, Xie T. Stem cell aging is controlled both intrinsically and extrinsically in the Drosophila Cell Stem Cell. 2007; 1:458-469.
5. Song X, Call GB, Kirilly D, Xie T. Notch signaling controls germline stem cell niche formation in the Drosophila ovary. Development. 2007; 134:1071-1080.
6. Jin Z, Xie T. Dcr-1 maintains Drosophila ovarian stem cells. Curr Biol. 2007; 17:539-544.
7. Xi R, Xie T. Stem cell self-renewal controlled by chromatin remodeling factors. Science. 2005; 310:1487-1489.
8. Kirilly D, Spana EP, Perrimon N, Padgett RW, Xie T. BMP signaling is required for controlling somatic stem cell self-renewal in the Drosophila ovary. Dev Cell. 2005; 9:651-662.
9. Song X, Xie T. DE-cadherin-mediated cell adhesion is essential for maintaining somatic stem cells in the Drosophila ovary. Proc Natl Acad Sci USA. 2002; 99:14813-14818.
10. Song X, Zhu CH, Doan C, Xie T. Germline stem cells anchored by adherens junctions in the Drosophila ovary niches. Science. 2002; 296:1855-1857.