Nanyang Assistant Professor Xia Yun
Principal Investigator, Stem Cell Lineage
Specification and Organ Regeneration Laboratory
Li Pin, Stem Cell Manager
Zhou Bingrui, PhD, Research Fellow
Zhang Tian, Research Assistant
Zheng Nan, Research Assistant
Assistant Professor Xia Yun is a Nanyang Assistant Professor at Lee Kong Chian School of Medicine, Nanyang Technological University. Prior to this appointment, Asst Prof Xia had her postdoctoral training at the world-renowned Salk Institute for Biological Studies, La Jolla, US. Asst Prof Xia obtained her BSc in Biology at China Agricultural University and her PhD in Molecular and Cell Biology at National University of Singapore.
Asst Prof Xia has been working on stem cell lineage specification with a special focus on generating kidney-related lineages. 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.
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; being 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 (3D) 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 develops 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 2-3 days in mouse. Whether residential adult kidney stem cells exist or not is a mystery that has been under debate for many years. How to make a non-regenerative organ regenerate? To address this question, Asst Prof Xia’s laboratory will employ multidisciplinary approaches using human pluripotent stem cells, genetic mouse model, and in vitro three-dimensional (3D) organoid culture system supplemented with organ specific extracellular matrix scaffolding technique.
In vitro differentiation
Differentiate human pluripotent stem cells into multiple kidney progenitors (MM, UB, and 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 3D kidney organoid from pluripotent stem cells with high efficiency (Figure 5); 2) modelling kidney diseases using 3D kidney organoid derived from patient-specific induced pluripotent stem cells; 3) evaluating the maturation of self-assembled kidney organoid upon transplantation beneath mouse renal capsule; 4) 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 limited capacity to repair the damage. 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 6). Research projects include: 1) identifying the cell types presenting survival, proliferating, and repair capacity (referred to as plastic population) upon acute kidney injury; 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.
Figure 1: Human-Mouse chimeric embryonic kidney organoid. Green: Human nuclei (labels ureteric bud progenitors derived from human H1 ESCs). Red: Cytokeratin8 (labels ureteric bud structure). Magenta: Six2 (labels condensed metanephric mesenchyme).
Figure 2: Implication of lineage reprogramming in multiple biological processes.
Figure 3: Scheme of mouse kidney development.
Figure 4: Scheme of in vitro lineage specification into multiple progenitors followed by organoid assembly and transplantation.
Figure 5: Kidney organoid derived from human Hes3 embryonic stem cells. Green: SYNPO (labels podocyte); Red: WT1 (labels podocyte); White: Cytokeratin (labels tubular structures); Blue: DAPI (labels nuclei).
Figure 6: Lineage reprogramming participates in kidney tissue homeostasis upon damage.
Li, Z., Araoka, T., Wu, J., Liao, H.-K., Li, M., Lazo, M., Zhou, B., Sui, Y., Wu, M.-Z., Tamura, I., Xia, Y., Beyret, E., Matsusaka, T., Pastan, I., Rodriguez Esteban, C., Guillen, I., Guillen, P., Campistol, J.M. and Izpsiua Belmonte, J.C. 2016. 3D culture supports long-term expansion of mouse and human nephrogenic progenitors. Cell Stem Cell.19(4):516-529.
Sancho-Martinez, I, Nivet, E, Xia, Y, Hishida, T, Aguirre, A, Ocampo, A, Ma, L, Morey, R, Krause, M, Zembrzycki, A, Ansorge, O, Vazquez-Ferrer, E, Dubova, I, Reddy, P, Lam, L, Hishida, Y, Wu, M, Rodriguez, C, O'Leary, D, Wahl, G, Verma, I, Laurent, L, Izpisua Belmonte, JC. 2016. Establishment of human iPSC-based models for the study and targeting of glioma initiating cells. Nat Comms.22(7):10743-757.
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.
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.
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.
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.
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.
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.
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.
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.