scholarly journals Osteocalcin expressing cells from tendon sheaths in mice contribute to tendon repair by activating Hedgehog signaling

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Yi Wang ◽  
Xu Zhang ◽  
Huihui Huang ◽  
Yin Xia ◽  
YiFei Yao ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Hedgehog Signaling ◽  
Progenitor Cell ◽  
Tendon Repair ◽  
Tendon Sheath ◽  
Lineage Tracing ◽  
Specific Marker ◽  
Molecular Function ◽  
Hh Signaling ◽  
Necessary And Sufficient

Both extrinsic and intrinsic tissues contribute to tendon repair, but the origin and molecular functions of extrinsic tissues in tendon repair are not fully understood. Here we show that tendon sheath cells harbor stem/progenitor cell properties and contribute to tendon repair by activating Hedgehog signaling. We found that Osteocalcin (Bglap) can be used as an adult tendon-sheath-specific marker in mice. Lineage tracing experiments show that Bglap-expressing cells in adult sheath tissues possess clonogenic and multipotent properties comparable to those of stem/progenitor cells isolated from tendon fibers. Transplantation of sheath tissues improves tendon repair. Mechanistically, Hh signaling in sheath tissues is necessary and sufficient to promote the proliferation of Mkx-expressing cells in sheath tissues, and its action is mediated through TGFβ/Smad3 signaling. Furthermore, co-localization of GLI1+ and MKX+ cells is also found in human tendinopathy specimens. Our work reveals the molecular function of Hh signaling in extrinsic sheath tissues for tendon repair.

scholarly journals Heterogeneity of murine periosteum osteochondroprogenitors involved in fracture healing

2020 ◽  
Author(s):  
Brya G Matthews ◽  
Francesca V Sbrana ◽  
Sanja Novak ◽  
Jessica L. Funnell ◽  
Ye Cao ◽  
...  
Keyword(s):  
Fracture Healing ◽  
Progenitor Cells ◽  
Progenitor Cell ◽  
Callus Formation ◽  
Lineage Tracing ◽  
Fracture Callus ◽  
Stem And Progenitor Cells ◽  
Periosteal Cells ◽  
Osteoblast Lineage

AbstractThe periosteum is the major source of cells involved in fracture healing. We sought to characterize differences in progenitor cell populations between periosteum and other bone compartments, and identify periosteal cells involved in fracture healing. The periosteum is highly enriched for progenitor cells, including Sca1+ cells, CFU-F and label-retaining cells. Lineage tracing with αSMACreER identifies periosteal cells that contribute to >80% of osteoblasts and ~40% of chondrocytes following fracture. A subset of αSMA+ cells are quiescent long-term injury-responsive progenitors. Ablation of αSMA+ cells impairs fracture callus formation. In addition, committed osteoblast-lineage cells contributed around 10% of osteoblasts, but no chondrocytes in fracture calluses. Most periosteal progenitors, particularly those that form osteoblasts, can be targeted by αSMACreER. We have demonstrated that the periosteum is highly enriched for skeletal stem and progenitor cells and there is heterogeneity in the populations of cells that contribute to mature lineages during periosteal fracture healing.

scholarly journals Mutations in thyroid hormone receptor α1 cause premature neurogenesis and progenitor cell depletion in human cortical development

2019 ◽  
Vol 116 (45) ◽  
pp. 22754-22763 ◽  
Author(s):  
Teresa G. Krieger ◽  
Carla M. Moran ◽  
Alberto Frangini ◽  
W. Edward Visser ◽  
Erik Schoenmakers ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Progenitor Cells ◽  
Hormone Receptor ◽  
Progenitor Cell ◽  
Thyroid Hormone Receptor ◽  
Cortical Development ◽  
Neural Progenitor Cell ◽  
Cortical Layer ◽  
Lineage Tracing

Mutations in the thyroid hormone receptor α 1 gene (THRA) have recently been identified as a cause of intellectual deficit in humans. Patients present with structural abnormalities including microencephaly, reduced cerebellar volume and decreased axonal density. Here, we show that directed differentiation of THRA mutant patient-derived induced pluripotent stem cells to forebrain neural progenitors is markedly reduced, but mutant progenitor cells can generate deep and upper cortical layer neurons and form functional neuronal networks. Quantitative lineage tracing shows that THRA mutation-containing progenitor cells exit the cell cycle prematurely, resulting in reduced clonal output. Using a micropatterned chip assay, we find that spatial self-organization of mutation-containing progenitor cells in vitro is impaired, consistent with down-regulated expression of cell–cell adhesion genes. These results reveal that thyroid hormone receptor α1 is required for normal neural progenitor cell proliferation in human cerebral cortical development. They also exemplify quantitative approaches for studying neurodevelopmental disorders using patient-derived cells in vitro.

scholarly journals Activated Hedgehog-GLI Signaling Causes Congenital Ureteropelvic Junction Obstruction

2017 ◽  
Vol 29 (2) ◽  
pp. 532-544 ◽  
Author(s):  
Sepideh Sheybani-Deloui ◽  
Lijun Chi ◽  
Marian V. Staite ◽  
Jason E. Cain ◽  
Brian J. Nieman ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Progenitor Cells ◽  
Hedgehog Signaling ◽  
Ureteropelvic Junction Obstruction ◽  
Lineage Tracing ◽  
Ureteropelvic Junction ◽  
Genetic Lineage ◽  
Intermediate Mesoderm ◽  
Renal Progenitors ◽  
Deficient Mice

Intrinsic ureteropelvic junction obstruction is the most common cause of congenital hydronephrosis, yet the underlying pathogenesis is undefined. Hedgehog proteins control morphogenesis by promoting GLI-dependent transcriptional activation and inhibiting the formation of the GLI3 transcriptional repressor. Hedgehog regulates differentiation and proliferation of ureteric smooth muscle progenitor cells during murine kidney-ureter development. Histopathologic findings of smooth muscle cell hypertrophy and stroma-like cells, consistently observed in obstructing tissue at the time of surgical correction, suggest that Hedgehog signaling is abnormally regulated during the genesis of congenital intrinsic ureteropelvic junction obstruction. Here, we demonstrate that constitutively active Hedgehog signaling in murine intermediate mesoderm–derived renal progenitors results in hydronephrosis and failure to develop a patent pelvic-ureteric junction. Tissue obstructing the ureteropelvic junction was marked as early as E13.5 by an ectopic population of cells expressing Ptch2, a Hedgehog signaling target. Constitutive expression of GLI3 repressor in Ptch1-deficient mice rescued ectopic Ptch2 expression and obstructive hydronephrosis. Whole transcriptome analysis of isolated Ptch2+ cells revealed coexpression of genes characteristic of stromal progenitor cells. Genetic lineage tracing indicated that stromal cells blocking the ureteropelvic junction were derived from intermediate mesoderm–derived renal progenitors and were distinct from the smooth muscle or epithelial lineages. Analysis of obstructive ureteric tissue resected from children with congenital intrinsic ureteropelvic junction obstruction revealed a molecular signature similar to that observed in Ptch1-deficient mice. Together, these results demonstrate a Hedgehog-dependent mechanism underlying mammalian intrinsic ureteropelvic junction obstruction.

Local progenitor cells shape the neoplastic vasculature and promote brain tumor growth.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14044-e14044
Author(s):  
Roland Kälin ◽  
Linzhi Cai ◽  
Dongxu Zhao ◽  
Huabin Zhang ◽  
Wenlong Zhang ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Brain Tumor ◽  
Brain Tumors ◽  
Single Cell ◽  
Progenitor Cells ◽  
Cell Population ◽  
Expression Profile ◽  
Progenitor Cell ◽  
Myeloid Cells ◽  
Lineage Tracing

e14044 Background: Aggressive brain tumors like glioblastoma depend on support by their local environment. While the role of tumor-associated myeloid cells on glioblastoma progression is well-documented, we have only partial knowledge of the pathological impact of glioblastoma -parenchymal progenitor cells. Methods: We investigated the glioblastoma microenvironment with transgenic lineage-tracing models ( nestin-creER2, R26-tdTomato and sox2-creER2,R26-tdTomato), intravital imaging, single-cell transcriptomics, immunofluorescence and flow-cytometry as well as histopathology and characterized a previously unknown tumor-associated progenitor cell. In functional experiments, we studied the knockout of the transcription factor SOX2 in these tumor-associated cells. Results: Lineage-traced cells from mouse glioblastoma were obtained by flow-cytometry and single cell transcriptomes compared to established gene expression data from brain tumor parenchymal cells. The traced tumor-associated cells had a transcriptomic profile largely resembling myeloid cells and expressed microglia-/macrophage-markers on the protein-level. However, transgenic models and bone-marrow chimera revealed that the traced cells were clearly distinct from microglia or macrophages. The traced tumor associated cells with a myeloid expression profile derived from a SOX2-dependent progenitor cell. Consequently, conditional Sox2-knockout ablated the entire myeloid-like cell population. Remarkably, this tumor-associated cell population had a large impact on disease-progression causing significant reduction of glioblastoma –vascularization to 53%, changing vascular function and leading to a decrease in tumor volume to 42% as compared to controls. The myeloid-like progenitor cells were identified in human brain tumors by immunofluorescence and in scRNA-seq data. Conclusions: We identified a previously unacknowledged population of tumor-associated progenitor cells with a myeloid-like expression profile that transiently appeared during glioblastoma growth. These progenitors have strong impact on glioblastoma progression and point towards a new and promising therapeutic target in order to support anti-angiogenic regimen in glioblastoma.

Hedgehog Signaling Is Dispensable for Adult Murine Hematopoiesis and Leukemogenesis.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1391-1391
Author(s):  
Inga Hofmann Zhang ◽  
Elizabeth H. Stover ◽  
Dana E. Cullen ◽  
Junhao Mao ◽  
Kelly J. Morgan ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Cell Fate ◽  
Intracellular Signaling ◽  
Hedgehog Signaling ◽  
Unexpected Finding ◽  
Hematopoietic Stem ◽  
Developmental Abnormalities ◽  
Hh Signaling ◽  
Pharmacologic Inhibition

Abstract Hedgehog (Hh) pathway proteins are a highly conserved family of intracellular signaling molecules that are critical for the development of multiple organs and tissues, and play a role in cell fate determination of self-renewing tissues in the adult. Mutations that impair Hh signaling have been associated with developmental abnormalities, and recent studies indicate that Hh plays an important role in hemangioblast formation and in adult hematopoiesis, as well as in the differentiation and proliferation of hematopoietic stem cells (HSC) and progenitor cells. We used a genetic and pharmacologic approach to define the role of the Hh pathway in adult hematopoiesis and leukemogenesis. We report the unexpected finding that loss of Hh signaling through conditional deletion of Smoothened (Smo) in the adult hematopoietic compartment has no effect on adult hematopoiesis, including peripheral blood count, number or cell cycle status of stem and progenitor cells, hematopoietic colony forming potential, long-term repopulating activity in competitive repopulation assays, or stress-response to serial 5-fluorouracil treatment. In support of these observations based on genetic inactivation of the pathway, we observed that pharmacologic inhibition of Hh signaling with a potent and highly selective small molecule antagonist of Smo has no apparent effect on hematopoiesis in the mouse in vivo. In addition, we observed that Hh signaling is not required for the development of MLL-AF9 mediated leukemia. Taken together, these data indicate that Hh signaling is dispensable for normal hematopoietic development and leukemogenesis, and that pharmacologic inhibition of Hh signaling, as a therapeutic strategy in treatment of solid tumors with constitutive Hh pathway activation is not likely to be associated with unmanageable hematopoietic toxicity.

scholarly journals Biphasic roles of hedgehog signaling in the production and self-renewal of outer radial glia in the ferret cerebral cortex

2021 ◽  
Author(s):  
Shirui Hou ◽  
Wan-Ling Ho ◽  
Lei Wang ◽  
Bryan Kuo ◽  
Jun Young Park ◽  
...  
Keyword(s):  
Hedgehog Signaling ◽  
Radial Glia ◽  
Superficial Layer ◽  
Cellular Mechanisms ◽  
Self Renewal ◽  
Layer Neuron ◽  
Outer Radial Glia ◽  
Hh Signaling ◽  
Necessary And Sufficient

The neocortex, the center for higher brain function, emerged in mammals and expanded in the course of evolution. The expansion of outer radial glia (oRGs) and intermediate progenitor cells (IPCs) plays key roles in the expansion and consequential folding of the neocortex. Therefore, understanding the mechanisms of oRG and IPC expansion is important for understanding neocortical development and evolution. By using mice and human cerebral organoids, we previously revealed that hedgehog (HH) signaling expands oRGs and IPCs. Nevertheless, it remained to be determined whether HH signaling expanded oRGs and IPCs in vivo in gyrencephalic species, in which oRGs and IPCs are naturally expanded. Here, we show that HH signaling is necessary and sufficient to expand oRGs and IPCs in ferrets, a gyrencephalic species, through conserved cellular mechanisms. HH signaling increases oRG-producing division modes of ventricular radial glia (vRGs), oRG self-renewal, and IPC proliferation. Notably, HH signaling affects vRG division modes only in an early restricted phase before superficial-layer neuron production peaks. Beyond this restricted phase, HH signaling promotes oRG self-renewal. Thus, HH signaling expands oRGs and IPCs in two distinct but continuous phases during cortical development.

scholarly journals The Adult Pituitary Shows Stem/Progenitor Cell Activation in Response to Injury and Is Capable of Regeneration

Endocrinology ◽  
2012 ◽  
Vol 153 (7) ◽  
pp. 3224-3235 ◽  
Author(s):  
Qiuli Fu ◽  
Lies Gremeaux ◽  
Raul M. Luque ◽  
Daisy Liekens ◽  
Jianghai Chen ◽  
...  
Keyword(s):  
Pituitary Gland ◽  
Progenitor Cells ◽  
Transcriptional Activation ◽  
Progenitor Cell ◽  
Cell Activation ◽  
Side Population ◽  
Lineage Tracing ◽  
Pituitary Cells ◽  
Adult Age ◽  
Gh Cells

The pituitary gland constitutes, together with the hypothalamus, the regulatory core of the endocrine system. Whether the gland is capable of cell regeneration after injury, in particular when suffered at adult age, is unknown. To investigate the adult pituitary's regenerative capacity and the response of its stem/progenitor cell compartment to damage, we constructed a transgenic mouse model to conditionally destroy pituitary cells. GHCre/iDTR mice express diphtheria toxin (DT) receptor after transcriptional activation by Cre recombinase, which is driven by the GH promoter. Treatment with DT for 3 d leads to gradual GH+ (somatotrope) cell obliteration with a final ablation grade of 80–90% 1 wk later. The stem/progenitor cell-clustering side population promptly expands after injury, concordant with the immediate increase in Sox2+ stem/progenitor cells. In addition, folliculo-stellate cells, previously designated as pituitary stem/progenitor cells and significantly overlapping with Sox2+ cells, also increase in abundance. In situ examination reveals expansion of the Sox2+ marginal-zone niche and appearance of remarkable Sox2+ cells that contain GH. When mice are left after the DT-provoked lesion, GH+ cells considerably regenerate during the following months. Double Sox2+/GH+ cells are observed throughout the regenerative period, suggesting recovery of somatotropes from stem/progenitor cells, as further supported by 5-ethynyl-2′-deoxyuridine (EdU) pulse-chase lineage tracing. In conclusion, our study demonstrates that the adult pituitary gland holds regenerative competence and that tissue repair follows prompt activation and plausible involvement of the stem/progenitor cells.

scholarly journals Mutations in thyroid hormone receptor α1 cause premature neurogenesis and progenitor cell depletion in human cortical development

2019 ◽  
Author(s):  
Teresa G Krieger ◽  
Carla M Moran ◽  
Alberto Frangini ◽  
W Edward Visser ◽  
Erik Schoenmakers ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Progenitor Cells ◽  
Hormone Receptor ◽  
Progenitor Cell ◽  
Thyroid Hormone Receptor ◽  
Cortical Development ◽  
Neural Progenitor Cell ◽  
Cortical Layer ◽  
Lineage Tracing

Mutations in the thyroid hormone receptor α 1 gene (THRA) have recently been identified as a cause of intellectual deficit in humans. Patients present with structural abnormalities including microcephaly, reduced cerebellar volume and decreased axonal density. Here, we show that directed differentiation of THRA mutant patient-derived iPSCs to forebrain neural progenitors is markedly reduced, but mutant progenitor cells can generate deep and upper cortical layer neurons and form functional neuronal networks. Quantitative lineage tracing shows that THRA mutation-containing progenitor cells exit the cell cycle prematurely, resulting in reduced clonal output. Using a novel micropatterned chip assay, we find that spatial self-organisation of mutation-containing progenitor cells is impaired, consistent with downregulated expression of cell-cell adhesion genes. These results reveal for the first time that thyroid hormone receptor α1 is required for normal neural progenitor cell proliferation and organisation in human cerebral cortical development. They also exemplify novel quantitative approaches for studying neurodevelopmental disorders using patient-derived cells in vitro.

scholarly journals Mesothelial cells are not a source of adipocytes in mice

2021 ◽  
Author(s):  
Gregory Westcott ◽  
Margo Emont ◽  
Jin Li ◽  
Christopher Jacobs ◽  
Linus Tsai ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Progenitor Cells ◽  
Adult Mouse ◽  
Wilms Tumor ◽  
Mesothelial Cells ◽  
Lineage Tracing ◽  
Specific Marker ◽  
Keratin 19 ◽  
Visceral Adipose ◽  
Tumor Gene

Visceral adipose tissue (VAT) depots are associated with the adverse metabolic consequences of obesity, such as insulin resistance. The developmental origin of VAT depots and the identity and regulation of adipocyte progenitor cells have been active areas of investigation. In recent years, a paradigm of mesothelial cells as a source of VAT adipocyte progenitor cells has emerged based on lineage-tracing studies using the Wilms' tumor gene, Wt1, as a marker for cells of mesothelial origin. Here we show that Wt1 expression in adipose tissue is not limited to the mesothelium, but is also expressed by a distinct preadipocyte population in both mice and humans. We identify keratin 19 (Krt19) as a highly-specific marker for the adult mouse mesothelium, and demonstrate that Krt19-expressing mesothelial cells do not differentiate into visceral adipocytes. These results contradict the assertion that the VAT mesothelium can serve as a source of adipocytes.

scholarly journals From Cell States to Cell Fates: How Cell Proliferation and Neuronal Differentiation Are Coordinated During Embryonic Development

2022 ◽  
Vol 15 ◽  
Author(s):  
Carla Belmonte-Mateos ◽  
Cristina Pujades
Keyword(s):  
Progenitor Cells ◽  
Progenitor Cell ◽  
New Technologies ◽  
Cell Lineage ◽  
Cell Types ◽  
Lineage Tracing ◽  
Vertebrate Brain ◽  
Proliferation And Differentiation ◽  
Cell Diversity ◽  
The Right

The central nervous system (CNS) exhibits an extraordinary diversity of neurons, with the right cell types and proportions at the appropriate sites. Thus, to produce brains with specific size and cell composition, the rates of proliferation and differentiation must be tightly coordinated and balanced during development. Early on, proliferation dominates; later on, the growth rate almost ceases as more cells differentiate and exit the cell cycle. Generation of cell diversity and morphogenesis takes place concomitantly. In the vertebrate brain, this results in dramatic changes in the position of progenitor cells and their neuronal derivatives, whereas in the spinal cord morphogenetic changes are not so important because the structure mainly grows by increasing its volume. Morphogenesis is under control of specific genetic programs that coordinately unfold over time; however, little is known about how they operate and impact in the pools of progenitor cells in the CNS. Thus, the spatiotemporal coordination of these processes is fundamental for generating functional neuronal networks. Some key aims in developmental neurobiology are to determine how cell diversity arises from pluripotent progenitor cells, and how the progenitor potential changes upon time. In this review, we will share our view on how the advance of new technologies provides novel data that challenge some of the current hypothesis. We will cover some of the latest studies on cell lineage tracing and clonal analyses addressing the role of distinct progenitor cell division modes in balancing the rate of proliferation and differentiation during brain morphogenesis. We will discuss different hypothesis proposed to explain how progenitor cell diversity is generated and how they challenged prevailing concepts and raised new questions.

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