Organ-specific patterns of myeloid cells may contribute tissue-specific growth and/or regenerative potentials. The perinatal stage of pancreas development marks a time characterized by maximal proliferation of pancreatic islets, ensuring the maintenance of glucose homeostasis throughout life. Ontogenically distinct CX3CR1+ and CCR2+ macrophage populations have been reported in the adult pancreas, but their functional contribution to islet cell growth at birth remains unknown. Here, we uncovered a temporally restricted requirement for CCR2+ myeloid cells in the perinatal proliferation of the endocrine pancreatic epithelium. CCR2+ macrophages are transiently enriched over CX3CR1+ subsets in the neonatal pancreas through both local expansion and recruitment of immature precursors. Using CCR2-specific depletion models, we show that loss of this myeloid population leads to a striking reduction in β cell proliferation, dysfunctional islet phenotypes, and glucose intolerance in newborns. Replenishment of pancreatic CCR2+ myeloid compartments by adoptive transfer rescues these defects. Gene profiling identifies pancreatic CCR2+ myeloid cells as a prominent source of IGF2, which contributes to IGF1R-mediated islet proliferation. These findings uncover proproliferative functions of CCR2+ myeloid subsets and identify myeloid-dependent regulation of IGF signaling as a local cue supporting pancreatic proliferation.
Kristin Mussar, Stephanie Pardike, Tobias M. Hohl, Gary Hardiman, Vincenzo Cirulli, Laura Crisa
β Cells are formed in embryonic life by differentiation of endocrine progenitors and expand by replication during neonatal life, followed by transition into functional maturity. In this study, we addressed the potential contribution of neuropeptide Y (NPY) in pancreatic β cell development and maturation. We show that NPY expression is restricted from the progenitor populations during pancreatic development and marks functionally immature β cells in fetal and neonatal mice and humans. NPY expression is epigenetically downregulated in β cells upon maturation. Neonatal β cells that express NPY are more replicative, and knockdown of NPY expression in neonatal mouse islets reduces replication and enhances insulin secretion in response to high glucose. These data show that NPY expression likely promotes replication and contributes to impaired glucose responsiveness in neonatal β cells. We show that NPY expression reemerges in β cells in mice fed with high-fat diet as well as in diabetes in mice and humans, establishing a potential new mechanism to explain impaired β cell maturity in diabetes. Together, these studies highlight the contribution of NPY in the regulation of β cell differentiation and have potential applications for β cell supplementation for diabetes therapy.
Pope Rodnoi, Mohan Rajkumar, Abu Saleh Md Moin, Senta K. Georgia, Alexandra E. Butler, Sangeeta Dhawan
A fundamental challenge to our understanding of brown adipose tissue (BAT) is the lack of an animal model that faithfully represents human BAT. Such a model is essential for direct assessment of the function and therapeutic potential of BAT depots in humans. In human adults, most of the thermoactive BAT depots are located in the supraclavicular region of the neck, while mouse studies focus on depots located in the interscapular region of the torso. We recently discovered BAT depots that are located in a region analogous to that of human supraclavicular BAT (scBAT). Here, we report that the mouse scBAT depot has morphological characteristics of classical BAT, possesses the potential for high thermogenic activity, and expresses a gene signature that is similar to that of human scBAT. Taken together, our studies reveal a mouse BAT depot that represents human BAT and provides a unique tool for developing new translatable approaches for utilizing human scBAT.
Qianxing Mo, Jordan Salley, Tony Roshan, Lisa A. Baer, Francis J. May, Eric J. Jaehnig, Adam C. Lehnig, Xin Guo, Qiang Tong, Alli M. Nuotio-Antar, Farnaz Shamsi, Yu-Hua Tseng, Kristin I. Stanford, Miao-Hsueh Chen
Many extremely preterm infants (born before 28 gestational weeks [GWs]) develop cognitive impairment in later life, although the underlying pathogenesis is not yet completely understood. Our examinations of the developing human neocortex confirmed that neuronal migration continues beyond 23 GWs, the gestational week at which extremely preterm infants have live births. We observed larger numbers of ectopic neurons in the white matter of the neocortex in human extremely preterm infants with brain injury and hypothesized that altered neuronal migration may be associated with cognitive impairment in later life. To confirm whether preterm brain injury affects neuronal migration, we produced brain damage in mouse embryos by occluding the maternal uterine arteries. The mice showed delayed neuronal migration, ectopic neurons in the white matter, altered neuronal alignment, and abnormal corticocortical axonal wiring. Similar to human extremely preterm infants with brain injury, the surviving mice exhibited cognitive deficits. Activation of the affected medial prefrontal cortices of the surviving mice improved working memory deficits, indicating that decreased neuronal activity caused the cognitive deficits. These findings suggest that altered neuronal migration altered by brain injury might contribute to the subsequent development of cognitive impairment in extremely preterm infants.
Ken-ichiro Kubo, Kimiko Deguchi, Taku Nagai, Yukiko Ito, Keitaro Yoshida, Toshihiro Endo, Seico Benner, Wei Shan, Ayako Kitazawa, Michihiko Aramaki, Kazuhiro Ishii, Minkyung Shin, Yuki Matsunaga, Kanehiro Hayashi, Masaki Kakeyama, Chiharu Tohyama, Kenji F. Tanaka, Kohichi Tanaka, Sachio Takashima, Masahiro Nakayama, Masayuki Itoh, Yukio Hirata, Barbara Antalffy, Dawna D. Armstrong, Kiyofumi Yamada, Ken Inoue, Kazunori Nakajima
During renal branching morphogenesis, ureteric bud tip cells (UBTC) serve as the progenitor epithelium for all cell types of the collecting duct. While the transcriptional circuitry of ureteric bud (UB) branching has been intensively studied, the transcriptional control of UBTC differentiation has been difficult to ascertain. This is partly due to limited knowledge of UBTC-specific transcription factors that mark the progenitor state. Here, we identify the transcription factor p63 (also known as TP63), a master regulator of basal stem cells in stratified epithelia, as a specific marker of mouse and human UBTC. Nuclear p63 marks Ret+ UBTC transiently and is silenced by the end of nephrogenesis. Lineage tracing revealed that a subset of UBTC expressing the ΔNp63 isoform (N-terminus truncated p63) is dedicated to generating cortical intercalated cells. Germline targeting of
Samir S. El-Dahr, Yuwen Li, Jiao Liu, Elleny Gutierrez, Kathleen S. Hering-Smith, Sabina Signoretti, Jean-Christophe Pignon, Satrajit Sinha, Zubaida Saifudeen
Mutations in the
Milena B. Furtado, Julia C. Wilmanns, Anjana Chandran, Joelle Perera, Olivia Hon, Christine Biben, Taylor J. Willow, Hieu T. Nim, Gurpreet Kaur, Stephanie Simonds, Qizhu Wu, David Willians, Ekaterina Salimova, Nicolas Plachta, James M. Denegre, Stephen A. Murray, Diane Fatkin, Michael Cowley, James T. Pearson, David Kaye, Mirana Ramialison, Richard P. Harvey, Nadia A. Rosenthal, Mauro W. Costa
Immaturity of the immune system of human fetuses and neonates is often invoked to explain their increased susceptibility to infection; however, the development of the fetal innate immune system in early life remains incompletely explored. We now show that the most mature NK cells found in adult (or postnatal) human circulation (CD94–CD16+) are absent during ontogeny. Human fetal NK cells were found to express the 2 signature T-box transcription factors essential for the development of all murine NK and NK-like cells, eomesodermin (Eomes) and T-bet. The single-cell pattern of Eomes and T-bet expression during ontogeny, however, revealed a stereotyped pattern of reciprocal dominance, with immature NK cells expressing higher amounts of Eomes and more mature NK cells marked by greater abundance of T-bet. We also observed a stereotyped pattern of tissue-specific NK cell maturation during human ontogeny, with fetal liver being more restrictive to NK cell maturity than fetal bone barrow, spleen, or lung. These results support the hypothesis that maturation of human NK cells has a discrete restriction until postnatal life, and provide a framework to better understand the increased susceptibility of fetuses and newborns to infection.
Amélie Collins, Nyanza Rothman, Kang Liu, Steven L. Reiner
It remains unclear how perturbations in cardiomyocyte sarcomere function alter postnatal heart development. We utilized murine models that allowed manipulation of cardiac myosin-binding protein C (MYBPC3) expression at critical stages of cardiac ontogeny to study the response of the postnatal heart to disrupted sarcomere function. We discovered that the hyperplastic to hypertrophic transition phase of mammalian heart development was altered in mice lacking MYBPC3 and this was the critical period for subsequent development of cardiomyopathy. Specifically, MYBPC3-null hearts developed evidence of increased cardiomyocyte endoreplication, which was accompanied by enhanced expression of cell cycle stimulatory cyclins and increased phosphorylation of retinoblastoma protein. Interestingly, this response was self-limited at later developmental time points by an upregulation of the cyclin-dependent kinase inhibitor p21. These results provide valuable insights into how alterations in sarcomere protein function modify postnatal heart development and highlight the potential for targeting cell cycle regulatory pathways to counteract cardiomyopathic stimuli.
Benjamin R. Nixon, Alexandra F. Williams, Michael S. Glennon, Alejandro E. de Feria, Sara C. Sebag, H. Scott Baldwin, Jason R. Becker
The neonatal mouse kidney retains nephron progenitor cells in a nephrogenic zone for 3 days after birth. We evaluated whether de novo nephrogenesis can be induced postnatally beyond 3 days. Given the long-term implications of nephron number for kidney health, it would be useful to enhance nephrogenesis in the neonate. We induced nephron reduction by cryoinjury with or without contralateral nephrectomy during the neonatal period or after 1 week of age. There was no detectable compensatory de novo nephrogenesis, as determined by glomerular counting and lineage tracing. Contralateral nephrectomy resulted in additional adaptive healing, with little or no fibrosis, but did not also stimulate de novo nephrogenesis. In contrast, injury initiated at 1 week of age led to healing with fibrosis. Thus, despite the presence of progenitor cells and ongoing nephron maturation in the newborn mouse kidney, de novo nephrogenesis is not inducible by acute nephron reduction. This indicates that additional nephron progenitors cannot be recruited after birth despite partial renal ablation providing a reparative stimulus and suggests that nephron number in the mouse is predetermined at birth.
Florian Tögel, M. Todd Valerius, Benjamin S. Freedman, Rossella Latrino, Mor Grinstein, Joseph V. Bonventre
Functional intestines are composed of cell types from all 3 primary germ layers and are generated through a highly orchestrated and serial developmental process. Directed differentiation of human pluripotent stem cells (hPSCs) has been shown to yield gut-specific cell types; however, these structures do not reproduce critical functional interactions between cell types of different germ layers. Here, we developed a simple protocol for the generation of mature functional intestinal organoids from hPSCs under xenogeneic-free conditions. The stem cell–derived gut organoids produced here were found to contain distinct types of intestinal cells, including enterocytes, goblet cells, Paneth cells, and enteroendocrine cells, that were derived from all 3 germ layers; moreover, they demonstrated intestinal functions, including peptide absorption, and showed innervated bowel movements in response to stimulation with histamine and anticholinergic drugs. Importantly, the gut organoids obtained using this xenogeneic-free system could be stably maintained in culture for prolonged periods and were successfully engrafted in vivo. Our xenogeneic-free approach for generating gut organoids from hPSCs provides a platform for studying human intestinal diseases and for pharmacological testing.
Hajime Uchida, Masakazu Machida, Takumi Miura, Tomoyuki Kawasaki, Takuya Okazaki, Kengo Sasaki, Seisuke Sakamoto, Noriaki Ohuchi, Mureo Kasahara, Akihiro Umezawa, Hidenori Akutsu
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