Browsing by Author "Lin, Yang"

Now showing 1 - 9 of 9
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    Bmi1 maintains the self-renewal property of innate-like B lymphocytes
    (American Association of Immunologists, 2020-06-15) Kobayashi, Michihiro; Lin, Yang; Mishra, Akansha; Shelly, Chris; Gao, Rui; Reeh, Colton W; Wang, Paul Zhiping; Xi, Rongwen; Liu, Yunlong; Wenzel, Pamela; Ghosn, Eliver; Liu, Yan; Yoshimoto, Momoko; Pediatrics, School of Medicine
    The self-renewal ability is a unique property of fetal-derived innate-like B-1a lymphocytes, which survive and function without being replenished by bone marrow (BM) progenitors. However, the mechanism by which IgM-secreting mature B-1a lymphocytes self-renew is poorly understood. In this study, we showed that Bmi1 was critically involved in this process. Although Bmi1 is considered essential for lymphopoiesis, the number of mature conventional B cells was not altered when Bmi1 was deleted in the B cell lineage. In contrast, the number of peritoneal B-1a cells was significantly reduced. Peritoneal cell transfer assays revealed diminished self-renewal ability of Bmi1-deleted B-1a cells, which was restored by additional deletion of Ink4-Arf, the well-known target of Bmi1 Fetal liver cells with B cell-specific Bmi1 deletion failed to repopulate peritoneal B-1a cells, but not other B-2 lymphocytes after transplantation assays, suggesting that Bmi1 may be involved in the developmental process of B-1 progenitors to mature B-1a cells. Although Bmi1 deletion has also been shown to alter the microenvironment for hematopoietic stem cells, fat-associated lymphoid clusters, the reported niche for B-1a cells, were not impaired in Bmi1 -/- mice. RNA expression profiling suggested lysine demethylase 5B (Kdm5b) as another possible target of Bmi1, which was elevated in Bmi1-/- B-1a cells in a stress setting and might repress B-1a cell proliferation. Our work has indicated that Bmi1 plays pivotal roles in self-renewal and maintenance of fetal-derived B-1a cells.
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    Differentiation, Evaluation, and Application of Human Induced Pluripotent Stem Cell–Derived Endothelial Cells
    (AHA, 2017-11) Lin, Yang; Gil, Chang-Hyun; Yoder, Mervin C.; Pediatrics, School of Medicine
    The emergence of induced pluripotent stem cell (iPSC) technology paves the way to generate large numbers of patient-specific endothelial cells (ECs) that can be potentially delivered for regenerative medicine in patients with cardiovascular disease. In the last decade, numerous protocols that differentiate EC from iPSC have been developed by many groups. In this review, we will discuss several common strategies that have been optimized for human iPSC-EC differentiation and subsequent studies that have evaluated the potential of human iPSC-EC as a cell therapy or as a tool in disease modeling. In addition, we will emphasize the importance of using in vivo vessel-forming ability and in vitro clonogenic colony–forming potential as a gold standard with which to evaluate the quality of human iPSC-EC derived from various protocols.
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    Functional B-1 progenitor cells are present in the hematopoietic stem cell-deficient embryo and depend on Cbfβ for their development
    (PNAS, 2014-08-19) Kobayashi, Michihiro; Shelley, W. Christopher; Seo, Wooseok; Vemula, Sasidhar; Lin, Yang; Liu, Yan; Kapur, Reuben; Taniuchi, Ichiro; Yoshimoto, Momoko; Department of Pediatrics, IU School of Medicine
    The fetal liver is a major hematopoietic site containing progenitor cells that give rise to nearly all blood cells, including B-1 cells. Because the fetal liver is not a de novo site of hematopoietic stem cell (HSC) or progenitor-cell emergence, it must be seeded by yolk sac (YS)-derived erythromyeloid progenitors at embryonic day (E) 8.5-E10 and aorta-gonado-mesonephros (AGM)-derived HSCs at E10.5-E11.5. Although the B-1 progenitor cell pool in the fetal liver is considered to be of HSC origin, we have previously proposed that YS-derived B-1 progenitors may also contribute to this pool. Until now, it has been impossible to determine whether HSC-independent B-1 progenitor cells exist in the fetal liver. Here, we demonstrate the presence of transplantable fetal-liver B-1 and marginal zone B progenitor cells in genetically engineered HSC-deficient embryos. HSC-deficient YS and AGM tissues produce B-1 progenitors in vitro and thus may serve as sites of origin for the B-1 progenitors that seed the fetal liver. Furthermore, we have found that core-binding factor beta (Cbfβ) expression is required for fetal-liver B-1 progenitor cell maturation and expansion. Our data provide, to our knowledge, the first evidence for the presence of B-1 progenitor cells in the fetal liver that arise independently of HSCs and implicate Cbfβ as a critical molecule in the development of this lineage.
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    Harnessing the NEON data revolution to advance open environmental science with a diverse and data-capable community
    (Wiley, 2021-12) Nagy, R. Chelsea; Balch, Jennifer K.; Bissell, Erin K.; Cattau, Megan E.; Glenn, Nancy F.; Halpern, Benjamin S.; Ilangakoon, Nayani; Johnson, Brian; Joseph, Maxwell B.; Marconi, Sergio; O’Riordan, Catherine; Sanovia, James; Swetnam, Tyson L.; Travis, William R.; Wasser, Leah A.; Woolner, Elizabeth; Zarnetske, Phoebe; Abdulrahim, Mujahid; Adler, John; Barnes, Grenville; Bartowitz, Kristina J.; Blake, Rachael E.; Bombaci, Sara P.; Brun, Julien; Buchanan, Jacob D.; Chadwick, K. Dana; Chapman, Melissa S.; Chong, Steven S.; Chung, Y. Anny; Corman, Jessica R.; Couret, Jannelle; Crispo, Erika; Doak, Thomas G.; Donnelly, Alison; Duffy, Katharyn A.; Dunning, Kelly H.; Duran, Sandra M.; Edmonds, Jennifer W.; Fairbanks, Dawson E.; Felton, Andrew J.; Florian, Christopher R.; Gann, Daniel; Gebhardt, Martha; Gill, Nathan S.; Gram, Wendy K.; Guo, Jessica S.; Harvey, Brian J.; Hayes, Katherine R.; Helmus, Matthew R.; Hensley, Robert T.; Hondula, Kelly L.; Huang, Tao; Hundertmark, Wiley J.; Iglesias, Virginia; Jacinthe, Pierre‐Andre; Jansen, Lara S.; Jarzyna, Marta A.; Johnson, Tiona M.; Jones, Katherine D.; Jones, Megan A.; Just, Michael G.; Kaddoura, Youssef O.; Kagawa‐Vivani, Aurora K.; Kaushik, Aleya; Keller, Adrienne B.; King, Katelyn B. S.; Kitzes, Justin; Koontz, Michael J.; Kouba, Paige V.; Kwan, Wai‐Yin; LaMontagne, Jalene M.; LaRue, Elizabeth A.; Li, Daijiang; Li, Bonan; Lin, Yang; Liptzin, Daniel; Long, William Alex; Mahood, Adam L.; Malloy, Samuel S.; Malone, Sparkle L.; McGlinchy, Joseph M.; Meier, Courtney L.; Melbourne, Brett A.; Mietkiewicz, Nathan; Morisette, Jeffery T.; Moustapha, Moussa; Muscarella, Chance; Musinsky, John; Muthukrishnan, Ranjan; Naithani, Kusum; Neely, Merrie; Norman, Kari; Parker, Stephanie M.; Perez Rocha, Mariana; Petri, Laís; Ramey, Colette A.; Record, Sydne; Rossi, Matthew W.; SanClements, Michael; Scholl, Victoria M.; Schweiger, Anna K.; Seyednasrollah, Bijan; Sihi, Debjani; Smith, Kathleen R.; Sokol, Eric R.; Spaulding, Sarah A.; Spiers, Anna I.; St. Denis, Lise A.; Staccone, Anika P.; Stack Whitney, Kaitlin; Stanitski, Diane M.; Stricker, Eva; Surasinghe, Thilina D.; Thomsen, Sarah K.; Vasek, Patrisse M.; Xiaolu, Li; Yang, Di; Yu, Rong; Yule, Kelsey M.; Zhu, Kai; Earth Sciences, School of Science
    It is a critical time to reflect on the National Ecological Observatory Network (NEON) science to date as well as envision what research can be done right now with NEON (and other) data and what training is needed to enable a diverse user community. NEON became fully operational in May 2019 and has pivoted from planning and construction to operation and maintenance. In this overview, the history of and foundational thinking around NEON are discussed. A framework of open science is described with a discussion of how NEON can be situated as part of a larger data constellation—across existing networks and different suites of ecological measurements and sensors. Next, a synthesis of early NEON science, based on >100 existing publications, funded proposal efforts, and emergent science at the very first NEON Science Summit (hosted by Earth Lab at the University of Colorado Boulder in October 2019) is provided. Key questions that the ecology community will address with NEON data in the next 10 yr are outlined, from understanding drivers of biodiversity across spatial and temporal scales to defining complex feedback mechanisms in human–environmental systems. Last, the essential elements needed to engage and support a diverse and inclusive NEON user community are highlighted: training resources and tools that are openly available, funding for broad community engagement initiatives, and a mechanism to share and advertise those opportunities. NEON users require both the skills to work with NEON data and the ecological or environmental science domain knowledge to understand and interpret them. This paper synthesizes early directions in the community’s use of NEON data, and opportunities for the next 10 yr of NEON operations in emergent science themes, open science best practices, education and training, and community building.
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    Identification of resident and circulating endothelial stem cells
    (2018-02) Lin, Yang; Yoder, Mervin C.
    Blood vessels and circulating blood contain rare immature endothelial cells that display in vitro clonal proliferative potential and in vivo vessel forming ability. However their precise location, origin, surface marker and molecular determinants have yet to be precisely defined. In this research body of work, we have identified ABCG2, an ATP binding cassette drug transporter that is expressed by stem cells of many lineages, to label vascular endothelial stem cells (VESC) and circulating endothelial stem cells (CESC). During development, ABCG2 expressing VESC are distributed in arterial, venous, and capillary vessels of multiple tissues including heart, lung, bone marrow and retina. They possess clonal colony forming potential in vitro and contribute to the growth of arteries, veins and capillaries in vivo. Steady state adult tissues also contain VESC that retain colony forming potential, though their frequency is decreased. In human umbilical vessels, ABCG2+ VSEC represent about 1% of umbilical cord vessel EC and showed higher colony forming potential than ABCG2- EC. In addition, CESC that could form EC colonies in vitro were identified from neonatal murine peripheral blood. About 30% of CESC were labeled by ABCG2. Lineage tracing experiments using hematopoietic (Flk2Cre) and EC (Tie2ERTCre) specific mice showed CESC were derived from vascular EC, not hematopoietic cells. CESC could participate (at a single cell level) in vessel formation in vivo in gel transplantation model. Furthermore, after transplantation, CESC retained secondary colony forming potential in formed blood vessels. Finally, we show that Abcg2 not only labels, but is also critical for the emergence/maintenance of VESC and the production of CESC. These findings provide a solid foundation to identify the critical roles of endothelial stem cells in vascular development, homeostasis and repair.
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    Long-Term Engraftment of ESC-Derived B-1 Progenitor Cells Supports HSC-Independent Lymphopoiesis
    (Elsevier, 2019-03-05) Lin, Yang; Kobayashi, Michihiro; Portilho, Nathalia Azevedo; Mishra, Akansha; Gao, Hongyu; Liu, Yunlong; Wenzel, Pamela; Davis, Brian; Yoder, Mervin C.; Yoshimoto, Momoko; Pediatrics, School of Medicine
    It is generally considered that mouse embryonic stem cell (ESC) differentiation into blood cells in vitro recapitulates yolk sac (YS) hematopoiesis. As such, similar to YS-derived B-progenitors, we demonstrate here that ESC-derived B-progenitors differentiate into B-1 and marginal zone B cells, but not B-2 cells in immunodeficient mice after transplantation. ESC-derived B-1 cells were maintained in the recipients for more than 6 months, secreting natural IgM antibodies in vivo. Gene expression profiling displayed a close relationship between ESC- and YS-derived B-1 progenitors. Because there are no hematopoietic stem cells (HSCs) detectable in our ESC differentiation culture, successful long-term engraftment of ESC-derived functional B-1 cells supports the presence of HSC-independent B-1 cell development.
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    Lymphoid progenitor emergence in the murine embryo and yolk sac precedes stem cell detection
    (Mary Ann Liebert, Inc., 2014-06-01) Lin, Yang; Yoder, Mervin C.; Yoshimoto, Momoko; Department of Pediatrics, IU School of Medicine
    Mammalian embryos produce several waves of hematopoietic cells before the establishment of the hematopoietic stem cell (HSC) hierarchy. These early waves of embryonic hematopoiesis present a reversed hierarchy in which hematopoietic potential is first displayed by highly specialized cells that are derived from transient uni- and bipotent progenitor cells. Hematopoiesis progresses through multilineage erythro-myeloid progenitor cells that lack self-renewal potential and, subsequently, to make distinct lymphoid progenitor cells before culminating in detectable definitive HSC. This review provides an overview of the stepwise development of embryonic hematopoiesis. We focus on recent progress in demonstrating that lymphoid lineages emerge from hemogenic endothelial cells before the presence of definitive HSC activity and discuss the implications of these findings.
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    Origin, prospective identification, and function of circulating endothelial colony-forming cells in mice and humans
    (The American Society for Clinical Investigation, 2023-03-08) Lin, Yang; Banno, Kimihiko; Gil, Chang-Hyun; Myslinski, Jered; Hato, Takashi; Shelley, William C.; Gao, Hongyu; Xuei, Xiaoling; Basile, David P.; Yoshimoto, Momoko; Prasain, Nutan; Tarnawsky, Stefan P.; Adams, Ralf H.; Naruse, Katsuhiko; Yoshida, Junko; Murphy, Michael P.; Horie, Kyoji; Yoder, Mervin C.; Pediatrics, School of Medicine
    Most circulating endothelial cells are apoptotic, but rare circulating endothelial colony-forming cells (C-ECFCs), also known as blood outgrowth endothelial cells, with proliferative and vasculogenic activity can be cultured; however, the origin and naive function of these C-ECFCs remains obscure. Herein, detailed lineage tracing revealed murine C-ECFCs emerged in the early postnatal period, displayed high vasculogenic potential with enriched frequency of clonal proliferative cells compared with tissue-resident ECFCs, and were not committed to or derived from the BM hematopoietic system but from tissue-resident ECFCs. In humans, C-ECFCs were present in the CD34bright cord blood mononuclear subset, possessed proliferative potential and in vivo vasculogenic function in a naive or cultured state, and displayed a single cell transcriptome sharing some umbilical venous endothelial cell features, such as a higher protein C receptor and extracellular matrix gene expression. This study provides an advance for the field by identifying the origin, naive function, and antigens to prospectively isolate C-ECFCs for translational studies.
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    Specific mesoderm subset derived from human pluripotent stem cells ameliorates microvascular pathology in type 2 diabetic mice
    (American Association for the Advancement of Science, 2022) Gil, Chang-Hyun; Chakraborty, Dibyendu; Vieira, Cristiano P.; Prasain, Nutan; Calzi, Sergio Li; Fortmann, Seth D.; Hu, Ping; Banno, Kimihiko; Jamal, Mohamed; Huang, Chao; Sielski, Micheli S.; Lin, Yang; Huang, Xinxin; Dupont, Mariana D.; Floyd, Jason L.; Prasad, Ram; Longhini, Ana Leda F.; McGill, Trevor J.; Chung, Hyung-Min; Murphy, Michael P.; Kotton, Darrell N.; Boulton, Michael E.; Yoder, Mervin C.; Grant, Maria B.; Pediatrics, School of Medicine
    Human induced pluripotent stem cells (hiPSCs) were differentiated into a specific mesoderm subset characterized by KDR+CD56+APLNR+ (KNA+) expression. KNA+ cells had high clonal proliferative potential and specification into endothelial colony-forming cell (ECFCs) phenotype. KNA+ cells differentiated into perfused blood vessels when implanted subcutaneously into the flank of nonobese diabetic/severe combined immunodeficient mice and when injected into the vitreous of type 2 diabetic mice (db/db mice). Transcriptomic analysis showed that differentiation of hiPSCs derived from diabetics into KNA+ cells was sufficient to change baseline differences in gene expression caused by the diabetic status and reprogram diabetic cells to a pattern similar to KNA+ cells derived from nondiabetic hiPSCs. Proteomic array studies performed on retinas of db/db mice injected with either control or diabetic donor-derived KNA+ cells showed correction of aberrant signaling in db/db retinas toward normal healthy retina. These data provide "proof of principle" that KNA+ cells restore perfusion and correct vascular dysfunction in db/db mice.