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Article: Therapeutic lymphangiogenesis after myocardial infarction: vascular endothelial growth factor-C paves the way.

Goichberg, Polina

2016 Volume 8, Issue 8, Page(s) 1904–1907

Language	English
Publishing date	2016-09-12
Publishing country	China
Document type	Comment ; Editorial
ZDB-ID	2573571-8
ISSN	2077-6624 ; 2072-1439
ISSN (online)	2077-6624
ISSN	2072-1439
DOI	10.21037/jtd.2016.07.34
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Article ; Online: Current Understanding of the Pathways Involved in Adult Stem and Progenitor Cell Migration for Tissue Homeostasis and Repair.

Goichberg, Polina

Stem cell reviews and reports

2016 Volume 12, Issue 4, Page(s) 421–437

Abstract: With the advancements in the field of adult stem and progenitor cells grows the recognition that the motility of primitive cells is a pivotal aspect of their functionality. There is accumulating evidence that the recruitment of tissue-resident and ... ...

Abstract	With the advancements in the field of adult stem and progenitor cells grows the recognition that the motility of primitive cells is a pivotal aspect of their functionality. There is accumulating evidence that the recruitment of tissue-resident and circulating cells is critical for organ homeostasis and effective injury responses, whereas the pathobiology of degenerative diseases, neoplasm and aging, might be rooted in the altered ability of immature cells to migrate. Furthermore, understanding the biological machinery determining the translocation patterns of tissue progenitors is of great relevance for the emerging methodologies for cell-based therapies and regenerative medicine. The present article provides an overview of studies addressing the physiological significance and diverse modes of stem and progenitor cell trafficking in adult mammalian organs, discusses the major microenvironmental cues regulating cell migration, and describes the implementation of live imaging approaches for the exploration of stem cell movement in tissues and the factors dictating the motility of endogenous and transplanted cells with regenerative potential.
MeSH term(s)	Adult ; Adult Stem Cells/cytology ; Adult Stem Cells/metabolism ; Cell Movement ; Homeostasis ; Humans ; Regenerative Medicine/methods ; Regenerative Medicine/trends ; Signal Transduction ; Stem Cell Transplantation/methods ; Stem Cell Transplantation/trends ; Stem Cells/cytology ; Stem Cells/metabolism ; Wounds and Injuries/metabolism ; Wounds and Injuries/physiopathology ; Wounds and Injuries/therapy
Language	English
Publishing date	2016-05-23
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2495577-2
ISSN	2629-3277 ; 1558-6804 ; 1550-8943
ISSN (online)	2629-3277 ; 1558-6804
ISSN	1550-8943
DOI	10.1007/s12015-016-9663-7
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Article ; Online: Phenotypically heterogeneous podoplanin-expressing cell populations are associated with the lymphatic vessel growth and fibrogenic responses in the acutely and chronically infarcted myocardium.

Cimini, Maria / Cannatá, Antonio / Pasquinelli, Gianandrea / Rota, Marcello / Goichberg, Polina

PloS one

2017 Volume 12, Issue 3, Page(s) e0173927

Abstract: Cardiac lymphatic vasculature undergoes substantial expansion in response to myocardial infarction (MI). However, there is limited information on the cellular mechanisms mediating post-MI lymphangiogenesis and accompanying fibrosis in the infarcted adult ...

Abstract	Cardiac lymphatic vasculature undergoes substantial expansion in response to myocardial infarction (MI). However, there is limited information on the cellular mechanisms mediating post-MI lymphangiogenesis and accompanying fibrosis in the infarcted adult heart. Using a mouse model of permanent coronary artery ligation, we examined spatiotemporal changes in the expression of lymphendothelial and mesenchymal markers in the acutely and chronically infarcted myocardium. We found that at the time of wound granulation, a three-fold increase in the frequency of podoplanin-labeled cells occurred in the infarcted hearts compared to non-operated and sham-operated counterparts. Podoplanin immunoreactivity detected LYVE-1-positive lymphatic vessels, as well as masses of LYVE-1-negative cells dispersed between myocytes, predominantly in the vicinity of the infarcted region. Podoplanin-carrying populations displayed a mesenchymal progenitor marker PDGFRα, and intermittently expressed Prox-1, a master regulator of the lymphatic endothelial fate. At the stages of scar formation and maturation, concomitantly with the enlargement of lymphatic network in the injured myocardium, the podoplanin-rich LYVE-1-negative multicellular assemblies were apparent in the fibrotic area, aligned with extracellular matrix deposits, or located in immediate proximity to activated blood vessels with high VEGFR-2 content. Of note, these podoplanin-containing cells acquired the expression of PDGFRβ or a hematoendothelial epitope CD34. Although Prox-1 labeling was abundant in the area affected by MI, the podoplanin-presenting cells were not consistently Prox-1-positive. The concordance of podoplanin with VEGFR-3 similarly varied. Thus, our data reveal previously unknown phenotypic and structural heterogeneity within the podoplanin-positive cell compartment in the infarcted heart, and suggest an alternate ability of podoplanin-presenting cardiac cells to generate lymphatic endothelium and pro-fibrotic cells, contributing to scar development.
MeSH term(s)	Animals ; Female ; Flow Cytometry ; Lymphangiogenesis/physiology ; Lymphatic Vessels/physiology ; Membrane Glycoproteins/metabolism ; Mice, Inbred C57BL ; Mice, Transgenic ; Myocardial Infarction/pathology ; Myocardium/cytology ; Myocardium/metabolism ; Myocardium/pathology ; Time Factors
Chemical Substances	Membrane Glycoproteins ; PDPN protein, human
Language	English
Publishing date	2017-03-23
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0173927
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Article ; Online: Aging Effects on Cardiac Progenitor Cell Physiology.

Rota, Marcello / Goichberg, Polina / Anversa, Piero / Leri, Annarosa

Comprehensive Physiology

2015 Volume 5, Issue 4, Page(s) 1775–1814

Abstract: Cardiac aging has been confounded by the concept that the heart is a postmitotic organ characterized by a predetermined number of myocytes, which is established at birth and largely preserved throughout life until death of the organ and organism. Based ... ...

Abstract	Cardiac aging has been confounded by the concept that the heart is a postmitotic organ characterized by a predetermined number of myocytes, which is established at birth and largely preserved throughout life until death of the organ and organism. Based on this premise, the age of cardiac cells should coincide with that of the organism; at any given time, the heart would be composed of a homogeneous population of myocytes of identical age. The discovery that stem cells reside in the heart and generate cardiac cell lineages has imposed a reconsideration of the mechanisms implicated in the manifestations of the aging myopathy. The progressive alterations of terminally differentiated myocytes, and vascular smooth muscle cells and endothelial cells may represent an epiphenomenon dictated by aging effects on cardiac progenitor cells (CPCs). Changes in the properties of CPCs with time may involve loss of self-renewing capacity, increased symmetric division with formation of daughter committed cells, partial depletion of the primitive pool, biased differentiation to the fibroblast fate, impaired ability to migrate, and forced entry into an irreversible quiescent state. Telomere shortening is a major variable of cellular senescence and organ aging, and support the notion that CPCs with critically shortened or dysfunctional telomeres contribute to myocardial aging and chronic heart failure. These defects constitute the critical variables that define the aging myopathy in humans. Importantly, a compartment of functionally competent human CPCs persists in the decompensated heart pointing to stem cell therapy as a novel form of treatment for the aging myopathy.
MeSH term(s)	Animals ; Cellular Senescence ; Heart/growth & development ; Heart/physiology ; Humans ; Myoblasts, Cardiac/cytology ; Myoblasts, Cardiac/metabolism ; Myoblasts, Cardiac/physiology ; Myocytes, Cardiac/cytology ; Myocytes, Cardiac/metabolism ; Myocytes, Cardiac/physiology
Language	English
Publishing date	2015-09-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ISSN	2040-4603
ISSN (online)	2040-4603
DOI	10.1002/cphy.c140082
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Article ; Online: Cardiac stem cells: biology and clinical applications.

Goichberg, Polina / Chang, Jerway / Liao, Ronglih / Leri, Annarosa

Antioxidants & redox signaling

2014 Volume 21, Issue 14, Page(s) 2002–2017

Abstract: Significance: Heart disease is the primary cause of death in the industrialized world. Cardiac failure is dictated by an uncompensated reduction in the number of viable and fully functional cardiomyocytes. While current pharmacological therapies ... ...

Abstract	Significance: Heart disease is the primary cause of death in the industrialized world. Cardiac failure is dictated by an uncompensated reduction in the number of viable and fully functional cardiomyocytes. While current pharmacological therapies alleviate the symptoms associated with cardiac deterioration, heart transplantation remains the only therapy for advanced heart failure. Therefore, there is a pressing need for novel therapeutic modalities. Cell-based therapies involving cardiac stem cells (CSCs) constitute a promising emerging approach for the replenishment of the lost tissue and the restoration of cardiac contractility. Recent advances: CSCs reside in the adult heart and govern myocardial homeostasis and repair after injury by producing new cardiomyocytes and vascular structures. In the last decade, different classes of immature cells expressing distinct stem cell markers have been identified and characterized in terms of their growth properties, differentiation potential, and regenerative ability. Phase I clinical trials, employing autologous CSCs in patients with ischemic cardiomyopathy, are being completed with encouraging results. Critical issues: Accumulating evidence concerning the role of CSCs in heart regeneration imposes a reconsideration of the mechanisms of cardiac aging and the etiology of heart failure. Deciphering the molecular pathways that prevent activation of CSCs in their environment and understanding the processes that affect CSC survival and regenerative function with cardiac pathologies, commonly accompanied by alterations in redox conditions, are of great clinical importance. Future directions: Further investigations of CSC biology may be translated into highly effective and novel therapeutic strategies aiming at the enhancement of the endogenous healing capacity of the diseased heart.
MeSH term(s)	Cell Differentiation/genetics ; Cell- and Tissue-Based Therapy ; Heart Diseases/genetics ; Heart Diseases/pathology ; Heart Diseases/therapy ; Humans ; Myocardial Infarction/genetics ; Myocardial Infarction/pathology ; Myocardial Infarction/therapy ; Myocardium/pathology ; Myocytes, Cardiac/cytology ; Stem Cell Transplantation ; Stem Cells/cytology
Language	English
Publishing date	2014-04-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1483836-9
ISSN	1557-7716 ; 1523-0864
ISSN (online)	1557-7716
ISSN	1523-0864
DOI	10.1089/ars.2014.5875
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Article ; Online: A Novel Class of Human Cardiac Stem Cells.

Moccetti, Tiziano / Leri, Annarosa / Goichberg, Polina / Rota, Marcello / Anversa, Piero

Cardiology in review

2015 Volume 23, Issue 4, Page(s) 189–200

Abstract: Following the recognition that hematopoietic stem cells improve the outcome of myocardial infarction in animal models, bone marrow mononuclear cells, CD34-positive cells, and mesenchymal stromal cells have been introduced clinically. The intracoronary or ...

Abstract	Following the recognition that hematopoietic stem cells improve the outcome of myocardial infarction in animal models, bone marrow mononuclear cells, CD34-positive cells, and mesenchymal stromal cells have been introduced clinically. The intracoronary or intramyocardial injection of these cell classes has been shown to be safe and to produce a modest but significant enhancement in systolic function. However, the identification of resident cardiac stem cells in the human heart (hCSCs) has created great expectation concerning the potential implementation of this category of autologous cells for the management of the human disease. Although phase 1 clinical trials have been conducted with encouraging results, the search for the most powerful hCSC for myocardial regeneration is in its infancy. This manuscript discusses the efforts performed in our laboratory to characterize the critical biological variables that define the growth reserve of hCSCs. Based on the theory of the immortal DNA template, we propose that stem cells retaining the old DNA represent 1 of the most powerful cells for myocardial regeneration. Similarly, the expression of insulin-like growth factor-1 receptors in hCSCs recognizes a cell phenotype with superior replicating reserve. However, the impressive recovery in ventricular hemodynamics and anatomy mediated by clonal hCSCs carrying the "mother" DNA underscores the clinical relevance of this hCSC class for the treatment of human heart failure.
MeSH term(s)	Animals ; Heart Failure/therapy ; Humans ; Myocardial Infarction/therapy ; Stem Cell Transplantation/methods ; Stem Cells/cytology
Language	English
Publishing date	2015-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1294965-6
ISSN	1538-4683 ; 1061-5377
ISSN (online)	1538-4683
ISSN	1061-5377
DOI	10.1097/CRD.0000000000000064
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Article ; Online: Cardiac stem cell niches.

Leri, Annarosa / Rota, Marcello / Hosoda, Toru / Goichberg, Polina / Anversa, Piero

Stem cell research

2014 Volume 13, Issue 3 Pt B, Page(s) 631–646

Abstract: The critical role that stem cell niches have in cardiac homeostasis and myocardial repair following injury is the focus of this review. Cardiac niches represent specialized microdomains where the quiescent and activated state of resident stem cells is ... ...

Abstract	The critical role that stem cell niches have in cardiac homeostasis and myocardial repair following injury is the focus of this review. Cardiac niches represent specialized microdomains where the quiescent and activated state of resident stem cells is regulated. Alterations in niche function with aging and cardiac diseases result in abnormal sites of cardiomyogenesis and inadequate myocyte formation. The relevance of Notch1 signaling, gap-junction formation, HIF-1α and metabolic state in the regulation of stem cell growth and differentiation within the cardiac niches are discussed.
MeSH term(s)	Animals ; Heart/growth & development ; Heart/physiology ; Humans ; Myocardium/cytology ; Myocardium/metabolism ; Stem Cell Niche ; Stem Cells/cytology ; Stem Cells/metabolism
Language	English
Publishing date	2014-09-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2393143-7
ISSN	1876-7753 ; 1873-5061
ISSN (online)	1876-7753
ISSN	1873-5061
DOI	10.1016/j.scr.2014.09.001
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Article ; Online: Origin of cardiomyocytes in the adult heart.

Leri, Annarosa / Rota, Marcello / Pasqualini, Francesco S / Goichberg, Polina / Anversa, Piero

Circulation research

2015 Volume 116, Issue 1, Page(s) 150–166

Abstract: This review article discusses the mechanisms of cardiomyogenesis in the adult heart. They include the re-entry of cardiomyocytes into the cell cycle; dedifferentiation of pre-existing cardiomyocytes, which assume an immature replicating cell phenotype; ... ...

Abstract	This review article discusses the mechanisms of cardiomyogenesis in the adult heart. They include the re-entry of cardiomyocytes into the cell cycle; dedifferentiation of pre-existing cardiomyocytes, which assume an immature replicating cell phenotype; transdifferentiation of hematopoietic stem cells into cardiomyocytes; and cardiomyocytes derived from activation and lineage specification of resident cardiac stem cells. The recognition of the origin of cardiomyocytes is of critical importance for the development of strategies capable of enhancing the growth response of the myocardium; in fact, cell therapy for the decompensated heart has to be based on the acquisition of this fundamental biological knowledge.
MeSH term(s)	Adult ; Animals ; Cell Differentiation/physiology ; Heart/growth & development ; Hematopoietic Stem Cells/physiology ; Humans ; Myocytes, Cardiac/physiology ; Organogenesis/physiology
Language	English
Publishing date	2015-01-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80100-8
ISSN	1524-4571 ; 0009-7330 ; 0931-6876
ISSN (online)	1524-4571
ISSN	0009-7330 ; 0931-6876
DOI	10.1161/CIRCRESAHA.116.303595
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Article ; Online: LpMab-12 Established by CasMab Technology Specifically Detects Sialylated O-Glycan on Thr52 of Platelet Aggregation-Stimulating Domain of Human Podoplanin.

Kato, Yukinari / Ogasawara, Satoshi / Oki, Hiroharu / Goichberg, Polina / Honma, Ryusuke / Fujii, Yuki / Kaneko, Mika K

PloS one

2016 Volume 11, Issue 3, Page(s) e0152912

Abstract: Podoplanin (PDPN), also known as Aggrus, possesses three tandem repeat of platelet aggregation-stimulating (PLAG) domains in its N-terminus. Among the PLAG domains, sialylated O-glycan on Thr52 of PLAG3 is essential for the binding to C-type lectin-like ... ...

Abstract	Podoplanin (PDPN), also known as Aggrus, possesses three tandem repeat of platelet aggregation-stimulating (PLAG) domains in its N-terminus. Among the PLAG domains, sialylated O-glycan on Thr52 of PLAG3 is essential for the binding to C-type lectin-like receptor-2 (CLEC-2) and the platelet-aggregating activity of human PDPN (hPDPN). Although various anti-hPDPN monoclonal antibodies (mAbs) have been generated, no specific mAb has been reported to target the epitope containing glycosylated Thr52. We recently established CasMab technology to develop mAbs against glycosylated membrane proteins. Herein, we report the development of a novel anti-glycopeptide mAb (GpMab), LpMab-12. LpMab-12 detected endogenous hPDPN by flow cytometry. Immunohistochemical analyses also showed that hPDPN-expressing lymphatic endothelial and cancer cells were clearly labeled by LpMab-12. The minimal epitope of LpMab-12 was identified as Asp49-Pro53 of hPDPN. Furthermore, LpMab-12 reacted with the synthetic glycopeptide of hPDPN, corresponding to 38-54 amino acids (hpp3854: 38-EGGVAMPGAEDDVVTPG-54), which carries α2-6 sialylated N-acetyl-D-galactosamine (GalNAc) on Thr52. LpMab-12 did not recognize non-sialylated GalNAc-attached glycopeptide, indicating that sialylated GalNAc on Thr52 is necessary for the binding of LpMab-12 to hPDPN. Thus, LpMab-12 could serve as a new diagnostic tool for determining whether hPDPN possesses the sialylation on Thr52, a site-specific post-translational modification critical for the hPDPN association with CLEC-2.
MeSH term(s)	Animals ; Antibodies, Monoclonal, Murine-Derived/chemistry ; Antibodies, Monoclonal, Murine-Derived/immunology ; CHO Cells ; COS Cells ; Cercopithecus aethiops ; Cricetinae ; Cricetulus ; Humans ; Lectins, C-Type/chemistry ; Lectins, C-Type/genetics ; Lectins, C-Type/immunology ; Membrane Glycoproteins/chemistry ; Membrane Glycoproteins/genetics ; Membrane Glycoproteins/immunology ; N-Acetylneuraminic Acid/chemistry ; N-Acetylneuraminic Acid/genetics ; N-Acetylneuraminic Acid/immunology ; Protein Structure, Tertiary
Chemical Substances	Antibodies, Monoclonal, Murine-Derived ; CLEC2B protein, human ; Lectins, C-Type ; Membrane Glycoproteins ; PDPN protein, human ; N-Acetylneuraminic Acid (GZP2782OP0)
Language	English
Publishing date	2016-03-31
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0152912
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Article ; Online: Pathways implicated in stem cell migration: the SDF-1/CXCR4 axis.

Vagima, Yaron / Lapid, Kfir / Kollet, Orit / Goichberg, Polina / Alon, Ronen / Lapidot, Tsvee

Methods in molecular biology (Clifton, N.J.)

2011 Volume 750, Page(s) 277–289

Abstract: The hallmark of hematopoietic stem and progenitor cells (HSPCs) is their motility, which is essential for their function, such as recruitment upon demand. Stromal Derived Factor-1 (SDF-1, CXCL12) and its major receptor CXCR4 play major roles in stem cell ...

Abstract	The hallmark of hematopoietic stem and progenitor cells (HSPCs) is their motility, which is essential for their function, such as recruitment upon demand. Stromal Derived Factor-1 (SDF-1, CXCL12) and its major receptor CXCR4 play major roles in stem cell motility and development. In vitro migration assays, implicating either gradients or cell surface-bound forms of SDF-1, are easy to perform and provide vital information regarding directional and random stem cell motility, which correlate with their repopulation potential in clinical and experimental transplantations. In vivo stem cell homing to the bone marrow, their retention, engraftment, and egress to the circulation, all involve SDF-1/CXCR4 interactions. Finally, other stem cell features such as stem cell survival and proliferation, are also dependent on the SDF-1/CXCR4 axis.
MeSH term(s)	Animals ; Antigens, CD34/analysis ; Antigens, CD34/immunology ; Bone Marrow/immunology ; Bone Marrow/metabolism ; Cell Adhesion ; Cell Count ; Cell Migration Assays ; Cell Movement ; Cell Survival ; Cells, Cultured ; Chemokine CXCL12/immunology ; Chemokine CXCL12/metabolism ; Chemotaxis/physiology ; Colony-Forming Units Assay ; Flow Cytometry ; Graft Survival/immunology ; Hematopoietic Stem Cell Mobilization ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/physiology ; Humans ; Mice ; Receptors, CXCR4/immunology ; Receptors, CXCR4/metabolism ; Whole-Body Irradiation
Chemical Substances	Antigens, CD34 ; Chemokine CXCL12 ; Receptors, CXCR4
Language	English
Publishing date	2011
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-61779-145-1_19
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