Xia Yun

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Assistant Professor Xia Yun
PhD
Nanyang Assistant Professor
Principal Investigator, Stem Cell Lineage Specification and Organ Regeneration Laboratory
Laboratory Staff
  • Zhou Bingrui, PhD, Research Fellow
Introduction

Dr Xia Yun is an Assistant Professor at Lee Kong Chian School of Medicine, Nanyang Technological University. Prior to this appointment, Dr Xia had her postdoctoral training at the world-renowned Salk Institute for Biological Studies, La Jolla, US. Dr Xia obtained her BSc in Biology at China Agricultural University and her PhD in Molecular and Cell Biology at National University of Singapore. 

Dr Xia has been working on stem cell lineage specification with a special interest in kidney related cell types. Her recent work led to the establishment of a novel method to differentiate human pluripotent stem cells into kidney ureteric bud progenitor-like cells using chemically defined medium. The generated human kidney cells form chimeric ureteric bud structures upon co-culture with embryonic mouse kidney cells (Figure 1). Her studies have been published in Nature Cell Biology and Nature Protocols, and highlighted by Nature Reviews Nephrology and Faculty 1000.
 
Research Focus
Three principle processes, presenting different cellular function and identity, are implicated in sustaining a living individual: ’generation’ (development and stem cell differentiation), ‘degeneration’ (ageing, damage and disease), and ‘regeneration’ (tissue homeostasis and repair) (Figure 2). With the accumulation of knowledge and technologies pertaining lineage reprogramming, it is becoming clear that genetic and epigenetic manipulation of mammalian cells could potentially allow for the generation of cell type on demand; be it induced pluripotent stem cells, partially dedifferentiated progenitors, or fully differentiated somatic cells.
Given that the number of people suffering from end-stage renal disease (ESRD), a consequence of many conditions including genetic defects, diabetes, cardiovascular diseases, and hypertension, is increasing rapidly, alternative therapeutic methods other than dialysis and kidney transplantation are urgently needed. Human kidney is a complex organ comprised of approximately 30 different types of cells, the function of which is dependent on its three-dimensional structure. Kidney development entails a reciprocal induction between two progenitor populations, metanephric mesenchyme (MM) and ureteric bud (UB), both of which are originated from a thin strip of mesoderm termed intermediate mesoderm (Figure 3). Mouse genetic studies showed that MM develop into podocytes, proximal tubular, loop of Henle, distal tubular, and distal connecting tubular plumbing into the collecting system, which is entirely derived from UB (Figure 3). Vascular progenitors invade into the S-shape stage developing nephron to elaborate the renal vasculature system.
Mammalian kidney is defined as a non-regenerative organ ascribing to the depletion of embryonic kidney progenitors during 36 weeks gestation in human and neonatal 3-5 days in mouse. Whether residential adult kidney stem cells exist or not is a mystery that has been under many years debating. How to make a non-regenerative organ regenerate? To address this question, Dr Xia’s laboratory will employ multidisciplinary approaches using human and mouse pluripotent stem cells, genetic mouse model, and in vitro three-dimensional organoid culture system supplemented with organ specific extracellular matrix scaffolding technique.
In vitro differentiation
Differentiate human/mouse pluripotent stem cells into multiple kidney progenitors (MM, UB, Vascular progenitor), capable of self-assembling and further maturating into adult kidney-like structure upon transplantation (Figure 4). Research projects include: 1) developing novel approaches to generate kidney progenitors from pluripotent stem cells with high efficiency. Mouse embryonic stem cells derived from transgenic mice Hoxb7-YFP (mark UB population) and Six2-GFP (mark MM population) will suffice the screen and enrichment processes; 2) evaluating the maturation of self-assembled kidney organoid upon transplantation beneath mouse renal capsule; 3) studying the effect of murine kidney extracellular matrix organ scaffold on renal progenitor maturation and alignment upon cell seeding.
In vivo lineage reprogramming
Similar to many other non-regenerative organs, adult mammalian kidney has very limited capacity to repair itself. An emerging strategy, referred to as in vivo lineage reprogramming, aims at promoting a tissue’s capability for self-repair either by inducing the proliferation of residual cell or fate conversion of other cell types into the desired cell type (Figure 5). Research projects include: 1) identifying the cell types presenting strongest survival, proliferating, and repair capacity (referred to as plastic population); 2) genomic and epigenomic characterisation of the plastic population; 3) elucidating whether such capacity has correlation with different development stages and age groups; 4) investigating whether in vivo manipulation of lineage reprogramming could enhance the self-repair capacity of adult kidney beyond regular physiological range.
Tracing the developing kidney
Development biologists have described a clear picture of early kidney development, starting from the invasion of UB into MM to initiate morphogenesis (Figure 3). Nephron, the functional unit of kidney, is a long tubular structure with specialised segments in charge of specific function. Little is known about how the nascent nephron elongates and demarcates different segments (Figure 6). Lack of such knowledge hampers scientists from developing methods allowing for generation of terminally differentiated kidney cells. Research projects include:  1) studying the proliferation pattern of mouse nephron at different developmental stages from E14.5 to puberty; 2) using confetti transgenic mouse model to investigate the clonogenecity of tubular cells during nephron elongation; 3) investigating the role of asymmetric cell division in nephron tubular segmentation during the elongation process.
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Figure 1: Human-Mouse chimeric embryonic kidney organoid. Green: Human ureteric bud progenitors (Derived from human H1 ESCs). Red: Cytokeratin 8 labeling ureteric bud. Magenta: Six2 labeling condensed metanephric mesenchyme
 
 
Figure 2: Implication of lineage reprogramming in multiple biological processes.
 
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Figure 3: Scheme of mouse kidney development.

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Figure 4: Scheme of in vitro lineage specification into renal progenitors, and subsequent organoid assembly.
 
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Figure 5: Lineage reprogramming participates in kidney tissue homeostasis upon damage.
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Figure 6: Hypothesis of nephron elongation.
Key Publications

1.
Xia Y, Sancho-Martinez I, Nivet E, Rodriguez C, Campistol J, Izpisua Belmonte JC. 2014. The generation of
kidney organoids by differentiation of human pluripotent cells to ureteric bud progenitor-like cells. Nat Protoc. 9(11):2693-703.

2.
Pulecio J, Nivet E, Sancho-Martinez I, Vitaloni M, Guenechea G, Xia Y, Kurian L, Dubova I, Bueren J, Laricchia-Robbio L, Izpisua Belmonte JC. 2014. Conversion of human fibroblasts into monocyte-like progenitor cells. Stem Cells. 32(11):2923-38.

3.
Uzarski JS, Xia Y, Belmont JC, Weitheim JA. 2014. New strategies in kidney regeneration and tissue engineering. Current Opinion in Nephrology and Hypertension. 23(4):299-405.

4.
Xia Y, Nivet E, Sancho-Martinez I, Gallegos T, Suzuki K, Okamura D, Wu M, Dubova I, Rodriguez C, Montserrat N, Campistol J, Izpisua Belmonte JC. 2013. Directed differentiation of human pluripotent cells to ureteric bud kidney progenitor-like cells. Nat Cell Biol. 15(12):1507-15.

5.
Montserrat N, Nivet E, Sancho-Martinez I, Hishida T, Kumar S, Miquel L, Cortina C, Hishida Y, Xia Y, Esteban CR, Izpisua Belmonte JC. 2013. Reprogramming of human fibroblasts to pluripotency with lineage specifiers. Cell Stem Cell. 13(3):341-50. 

6.
Kurian L, Sancho-Martinez I, Nivet E, Aguirre A, Moon K, Pendaries C, Volle-Challier C, Bono F, Herbert JM, Pulecio J, Xia Y, Li M, Montserrat N, Ruiz S, Dubova I, Rodriguez C, Denli AM, Boscolo FS, Thiagarajan RD, Gage FH, Loring JF, Laurent LC, Izpisua Belmonte JC. 2013. Conversion of human fibroblasts to angioblast-like progenitor cells. Nat Methods. 10(1):77-83. 

7. Montserrat N, Ramírez-Bajo MJ, Xia Y, Sancho-Martinez I, Moya-Rull D, Miquel-Serra L, Yang S, Nivet E, Cortina C, González F, Izpisua Belmonte JC, Campistol JM. 2012. Generation of induced pluripotent stem cells from human renal proximal tubular cells with only two transcription factors, OCT4 and SOX2. J Biol Chem. 287(29):24131-8. 

8.
Ye F, Tan L, Yang Q, Xia Y, Deng LW, Murata-Hori M, Liou YC. 2011. HURP regulates chromosome congression by modulating kinesin Kif18A function. Curr Biol. 21(18):1584-91.

9.
Xia Y, Yang Q, Gong X, Ye F, Liou YC. 2011. Dose-dependent mutual regulation between Wip1 and p53 following UVC irradiation. Int J Biochem Cell Biol. 43(4):535-44.

10.
Xia Y, Ongusaha P, Lee SW, Liou YC. 2009. Loss of Wip1 sensitizes cells to stress- and DNA damage-induced apoptosis. J Biol Chem. 284(26):17428-37.