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Article ; Online: In vitro reconstructed 3D corneal tissue models for ocular toxicology and ophthalmic drug development.

Kaluzhny, Yulia / Klausner, Mitchell

In vitro cellular & developmental biology. Animal

2021 Volume 57, Issue 2, Page(s) 207–237

Abstract: Testing of all manufactured products and their ingredients for eye irritation is a regulatory requirement. In the last two decades, the development of alternatives to the in vivo Draize eye irritation test method has substantially advanced due to the ... ...

Abstract	Testing of all manufactured products and their ingredients for eye irritation is a regulatory requirement. In the last two decades, the development of alternatives to the in vivo Draize eye irritation test method has substantially advanced due to the improvements in primary cell isolation, cell culture techniques, and media, which have led to improved in vitro corneal tissue models and test methods. Most in vitro models for ocular toxicology attempt to reproduce the corneal epithelial tissue which consists of 4-5 layers of non-keratinized corneal epithelial cells that form tight junctions, thereby limiting the penetration of chemicals, xenobiotics, and pharmaceuticals. Also, significant efforts have been directed toward the development of more complex three-dimensional (3D) equivalents to study wound healing, drug permeation, and bioavailability. This review focuses on in vitro reconstructed 3D corneal tissue models and their utilization in ocular toxicology as well as their application to pharmacology and ophthalmic research. Current human 3D corneal epithelial cell culture models have replaced in vivo animal eye irritation tests for many applications, and substantial validation efforts are in progress to verify and approve alternative eye irritation tests for widespread use. The validation of drug absorption models and further development of models and test methods for many ophthalmic and ocular disease applications is required.
MeSH term(s)	Animals ; Cornea/anatomy & histology ; Cornea/physiology ; Drug Development ; Humans ; Models, Biological ; Ophthalmology ; Tissue Survival/physiology ; Toxicity Tests
Language	English
Publishing date	2021-02-05
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	1077810-x
ISSN	1543-706X ; 0883-8364 ; 1071-2690
ISSN (online)	1543-706X
ISSN	0883-8364 ; 1071-2690
DOI	10.1007/s11626-020-00533-7
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Article: In vitro reconstructed 3D corneal tissue models for ocular toxicology and ophthalmic drug development

Kaluzhny, Yulia / Klausner, Mitchell

In vitro cellular & developmental biology. 2021 Feb., v. 57, no. 2

2021

Abstract	Testing of all manufactured products and their ingredients for eye irritation is a regulatory requirement. In the last two decades, the development of alternatives to the in vivo Draize eye irritation test method has substantially advanced due to the improvements in primary cell isolation, cell culture techniques, and media, which have led to improved in vitro corneal tissue models and test methods. Most in vitro models for ocular toxicology attempt to reproduce the corneal epithelial tissue which consists of 4–5 layers of non-keratinized corneal epithelial cells that form tight junctions, thereby limiting the penetration of chemicals, xenobiotics, and pharmaceuticals. Also, significant efforts have been directed toward the development of more complex three-dimensional (3D) equivalents to study wound healing, drug permeation, and bioavailability. This review focuses on in vitro reconstructed 3D corneal tissue models and their utilization in ocular toxicology as well as their application to pharmacology and ophthalmic research. Current human 3D corneal epithelial cell culture models have replaced in vivo animal eye irritation tests for many applications, and substantial validation efforts are in progress to verify and approve alternative eye irritation tests for widespread use. The validation of drug absorption models and further development of models and test methods for many ophthalmic and ocular disease applications is required.
Keywords	bioavailability ; cell culture ; cornea ; drug development ; drugs ; epithelial cells ; epithelium ; eye diseases ; eye irritation ; humans ; permeability ; pharmacokinetics ; toxicology ; xenobiotics
Language	English
Dates of publication	2021-02
Size	p. 207-237.
Publishing place	Springer US
Document type	Article
Note	NAL-AP-2-clean ; Review
ISSN	1071-2690
DOI	10.1007/s11626-020-00533-7
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Comparison of In Vitro Corneal Permeation and In Vivo Ocular Bioavailability in Rabbits of Three Marketed Latanoprost Formulations.

Chauchat, Laure / Guerin, Camille / Kaluzhny, Yulia / Renard, Jean-Paul

European journal of drug metabolism and pharmacokinetics

2023 Volume 48, Issue 6, Page(s) 633–645

Abstract: Background and objective: All latanoprost formulations currently available for the treatment of glaucoma or ocular hypertension contain the same concentration of latanoprost (0.005%) but differ in excipients, which may affect corneal drug permeability ... ...

Abstract	Background and objective: All latanoprost formulations currently available for the treatment of glaucoma or ocular hypertension contain the same concentration of latanoprost (0.005%) but differ in excipients, which may affect corneal drug permeability or stability. This study aimed at comparing corneal penetration of three marketed latanoprost solutions with different excipient formulations in in vitro and in vivo drug permeability studies. Methods: Three latanoprost formulations were tested under good laboratory practice conditions: a formulation containing benzalkonium chloride (BAK) but no surfactant (Preserved latanoprost); the same formulation except preservative-free (PF) without BAK or surfactant (SF) (PF SF latanoprost); and a different formulation without BAK but containing a non-ionic surfactant (MGHS 40 at 5%) combined with thickening agents (Carbomer 974P, Macrogol 4000) (PF latanoprost). Corneal permeation of latanoprost acid (LAT) was first determined in vitro using a reconstructed human corneal epithelium tissue. Then, in vivo pharmacokinetic studies were performed on pigmented rabbits, for which LAT concentration was measured in the aqueous humour (AH) and iris-ciliary body (ICB). Results: In vitro, the cumulative transport of LAT was linear between 1 h and 4 h for preserved latanoprost and PF SF latanoprost, and LAT concentrations matched exactly at each timepoint. By contrast, the permeation of PF latanoprost was linear between 2 h and 12 h and was significantly lower than that of preserved latanoprost and PF SF latanoprost at 4 and 8 h (p < 0.001). In rabbits, the concentrations of LAT in AH and ICB were not statistically different between preserved latanoprost and PF SF latanoprost at each timepoint, except at 1 h in ICB (p = 0.005). By comparison, the LAT concentration of PF latanoprost was statistically (p < 0.05) lower than that of preserved latanoprost and PF SF latanoprost in AH and ICB from 0.5 to 3 h. Conclusion: BAK did not influence the corneal penetration of latanoprost in in vitro and in vivo studies. The formulation containing a non-ionic surfactant resulted in lower and slower ocular penetration compared with preserved or PF SF formulations. This raises questions about the relevance of BAK and some surfactants in enhancing corneal penetration of ocular formulations.
MeSH term(s)	Humans ; Animals ; Rabbits ; Latanoprost ; Biological Availability ; Prostaglandins F, Synthetic/therapeutic use ; Ophthalmic Solutions ; Antihypertensive Agents ; Preservatives, Pharmaceutical ; Surface-Active Agents
Chemical Substances	Latanoprost (6Z5B6HVF6O) ; Prostaglandins F, Synthetic ; Ophthalmic Solutions ; Antihypertensive Agents ; Preservatives, Pharmaceutical ; Surface-Active Agents
Language	English
Publishing date	2023-09-08
Publishing country	France
Document type	Journal Article
ZDB-ID	196729-0
ISSN	2107-0180 ; 0398-7639 ; 0378-7966
ISSN (online)	2107-0180
ISSN	0398-7639 ; 0378-7966
DOI	10.1007/s13318-023-00853-5
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Zs.A 1236: Show issues

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Article ; Online: Evaluation of in vitro rat and human airway epithelial models for acute inhalation toxicity testing.

Wallace, Joanne / Jackson, George R / Kaluzhny, Yulia / Ayehunie, Seyoum / Lansley, Alison B / Roper, Clive / Hayden, Patrick J

Toxicological sciences : an official journal of the Society of Toxicology

2023 Volume 194, Issue 2, Page(s) 178–190

Abstract: In vivo models (mostly rodents) are currently accepted by regulatory authorities for assessing acute inhalation toxicity. Considerable efforts have been made in recent years to evaluate in vitro human airway epithelial models (HAEM) as replacements for ... ...

Abstract	In vivo models (mostly rodents) are currently accepted by regulatory authorities for assessing acute inhalation toxicity. Considerable efforts have been made in recent years to evaluate in vitro human airway epithelial models (HAEM) as replacements for in vivo testing. In the current work, an organotypic in vitro rat airway epithelial model (RAEM), rat EpiAirway, was developed and characterized to allow a direct comparison with the available HAEM, human EpiAirway, in order to address potential interspecies variability in responses to harmful agents. The rat and human models were evaluated in 2 independent laboratories with 14 reference chemicals, selected to cover a broad range of chemical structures and reactive groups, as well as known acute animal and human toxicity responses, in 3 replicate rounds of experiments. Toxicity endpoints included changes in tissue viability (MTT assay), epithelial barrier integrity (TEER, transepithelial electrical resistance), and tissue morphology (histopathology). The newly developed rat EpiAirway model produced reproducible results across all replicate experiments in both testing laboratories. Furthermore, a high level of concordance was observed between the RAEM and HAEM toxicity responses (determined by IC25) in both laboratories, with R2=0.78 and 0.88 when analyzed by TEER; and R2=0.92 for both when analyzed by MTT. These results indicate that rat and human airway epithelial tissues respond similarly to acute exposures to chemicals. The new in vitro RAEM will help extrapolate to in vivo rat toxicity responses and support screening as part of a 3Rs program.
MeSH term(s)	Humans ; Rats ; Animals ; Anemia, Refractory, with Excess of Blasts ; Respiratory System ; Administration, Inhalation ; Epithelium ; Heme
Chemical Substances	Heme (42VZT0U6YR)
Language	English
Publishing date	2023-06-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfad058
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Article: Optimization and Characterization of Novel ALCAM-Targeting Antibody Fragments for Transepithelial Delivery.

Bauer, Aline / Klassa, Sven / Herbst, Anja / Maccioni, Cristina / Abhamon, William / Segueni, Noria / Kaluzhny, Yulia / Hunter, Morgan Campbell / Halin, Cornelia

Pharmaceutics

2023 Volume 15, Issue 7

Abstract: Activated leukocyte cell adhesion molecule (ALCAM) is a cell adhesion molecule that supports T cell activation, leukocyte migration, and (lymph)angiogenesis and has been shown to contribute to the pathology of various immune-mediated disorders, including ...

Abstract	Activated leukocyte cell adhesion molecule (ALCAM) is a cell adhesion molecule that supports T cell activation, leukocyte migration, and (lymph)angiogenesis and has been shown to contribute to the pathology of various immune-mediated disorders, including asthma and corneal graft rejection. In contrast to monoclonal antibodies (mAbs) targeting ALCAM's T cell expressed binding partner CD6, no ALCAM-targeting mAbs have thus far entered clinical development. This is likely linked with the broad expression of ALCAM on many different cell types, which increases the risk of eliciting unwanted treatment-induced side effects upon systemic mAb application. Targeting ALCAM in surface-exposed tissues, such as the lungs or the cornea, by a topical application could circumvent this issue. Here, we report the development of various stability- and affinity-improved anti-ALCAM mAb fragments with cross-species reactivity towards mouse, rat, monkey, and human ALCAM. Fragments generated in either mono- or bivalent formats potently blocked ALCAM-CD6 interactions in a competition ELISA, but only bivalent fragments efficiently inhibited ALCAM-ALCAM interactions in a leukocyte transmigration assay. The different fragments displayed a clear size-dependence in their ability to penetrate the human corneal epithelium. Furthermore, intranasal delivery of anti-ALCAM fragments reduced leukocyte infiltration in a mouse model of asthma, confirming ALCAM as a target for topical application in the lungs.
Language	English
Publishing date	2023-06-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics15071841
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Article ; Online: Oxidative stress in corneal injuries of different origin: Utilization of 3D human corneal epithelial tissue model.

Kaluzhny, Yulia / Kinuthia, Miriam W / Lapointe, Allison M / Truong, Thoa / Klausner, Mitchell / Hayden, Patrick

Experimental eye research

2019 Volume 190, Page(s) 107867

Abstract: The purpose of the current work was to utilize a three dimensional (3D) corneal epithelial tissue model to study dry eye disease and oxidative stress-related corneal epithelial injuries for the advancement of ocular therapeutics. Air-liquid interface ... ...

Abstract	The purpose of the current work was to utilize a three dimensional (3D) corneal epithelial tissue model to study dry eye disease and oxidative stress-related corneal epithelial injuries for the advancement of ocular therapeutics. Air-liquid interface cultures of normal human corneal epithelial cells were used to produce 3D corneal epithelial tissues appropriate for physiologically relevant exposure to environmental factors. Oxidative stress was generated by exposing the tissues to non-toxic doses of ultraviolet radiation (UV), hydrogen peroxide, vesicating agent nitrogen mustard, or desiccating conditions that stimulated morphological, cellular, and molecular changes relevant to dry eye disease. Corneal specific responses, including barrier function, tissue viability, reactive oxygen species (ROS) accumulation, lipid peroxidation, cytokine release, histology, and gene expression were evaluated. 3D corneal epithelial tissue model structurally and functionally reproduced key features of molecular responses of various types of oxidative stress-induced ocular damage. The most pronounced effects for different treatments were: UV irradiation - intracellular ROS accumulation; hydrogen peroxide exposure - barrier impairment and IL-8 release; nitrogen mustard exposure - lipid peroxidation and IL-8 release; desiccating conditions - tissue thinning, a decline in mucin expression, increased lipid peroxidation and IL-8 release. Utilizing a PCR gene array, we compared the effects of corneal epithelial damage on the expression of 84 oxidative stress-responsive genes and found specific molecular responses for each type of damage. The topical application of lubricant eye drops improved tissue morphology while decreasing lipid peroxidation and IL-8 release from tissues incubated at desiccating conditions. This model is anticipated to be a valuable tool to study molecular mechanisms of corneal epithelial damage and aid in the development of therapies against dry eye disease, oxidative stress- and vesicant-induced ocular injuries.
MeSH term(s)	Alkylating Agents/toxicity ; Cell Survival ; Corneal Injuries/etiology ; Corneal Injuries/metabolism ; Cytokines/metabolism ; Dry Eye Syndromes/etiology ; Dry Eye Syndromes/metabolism ; Electric Impedance ; Epithelium, Corneal/drug effects ; Epithelium, Corneal/metabolism ; Epithelium, Corneal/radiation effects ; Fluorescent Antibody Technique, Indirect ; Humans ; Hydrogen Peroxide/toxicity ; Imaging, Three-Dimensional ; Lipid Peroxidation/physiology ; Mechlorethamine/toxicity ; Models, Biological ; Oxidants/toxicity ; Oxidative Stress/physiology ; Reactive Oxygen Species/metabolism ; Real-Time Polymerase Chain Reaction ; Ultraviolet Rays/adverse effects
Chemical Substances	Alkylating Agents ; Cytokines ; Oxidants ; Reactive Oxygen Species ; Mechlorethamine (50D9XSG0VR) ; Hydrogen Peroxide (BBX060AN9V)
Language	English
Publishing date	2019-11-06
Publishing country	England
Document type	Journal Article
ZDB-ID	80122-7
ISSN	1096-0007 ; 0014-4835
ISSN (online)	1096-0007
ISSN	0014-4835
DOI	10.1016/j.exer.2019.107867
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Article ; Online: New Human Organotypic Corneal Tissue Model for Ophthalmic Drug Delivery Studies.

Kaluzhny, Yulia / Kinuthia, Miriam W / Truong, Thoa / Lapointe, Allison M / Hayden, Patrick / Klausner, Mitchell

Investigative ophthalmology & visual science

2018 Volume 59, Issue 7, Page(s) 2880–2898

Abstract: Purpose: The purpose of the current work was to develop a physiologically relevant, in vitro human three-dimensional (3D) corneal epithelial tissue model for use in ophthalmic drug development.: Methods: Normal human corneal epithelial cells were ... ...

Abstract	Purpose: The purpose of the current work was to develop a physiologically relevant, in vitro human three-dimensional (3D) corneal epithelial tissue model for use in ophthalmic drug development. Methods: Normal human corneal epithelial cells were cultured at the air-liquid interface to produce the 3D corneal tissue model. Corneal barrier was determined by measuring transepithelial electrical resistance (TEER). Quantitative PCR arrays were utilized to investigate expression of 84 phase I/II metabolizing enzymes and 84 drug transporter genes. Permeability was evaluated using model compounds with a wide range of hydrophobicity, molecular weight, and excipients. Finally, different formulations of latanoprost and bimatoprost were administered and drug absorption and tissue viability and integrity were investigated. Results: Histologic assessment and TEER of the corneal tissue model revealed tissue structure, thickness, and barrier formation (1000 ± 146 Ω·cm2) comparable to native human corneal epithelium. The 3D corneal tissue expressed tight junctions, mucins, and key corneal epithelial detoxification enzymes. Drug-metabolizing enzyme and transporter gene expression in 3D corneal tissue and excised human corneal epithelium were highly correlated (r2 = 0.87). Coefficients of permeation for model drugs in the tissue model and excised rabbit corneas also showed a high correlation (r2 = 0.94). As expected, latanoprost and bimatoprost free acids had much lower permeability (Papp = 1.2 × 10-6 and 1.9 × 10-6) than the corresponding prodrugs (Papp = 2.5 × 10-5 and 5.6 × 10-5), respectively. The presence of 0.02% benzalkonium chloride in ophthalmic formulations significantly affected tissue barrier and viability. Conclusions: The newly developed 3D corneal tissue model appears to be very useful for evaluation of corneal drug permeability and safety during ophthalmic drug development.
MeSH term(s)	Antihypertensive Agents/pharmacokinetics ; Bimatoprost/pharmacokinetics ; Biological Transport ; Cell Survival ; Cells, Cultured ; Drug Delivery Systems ; Electric Impedance ; Epithelium, Corneal/cytology ; Epithelium, Corneal/metabolism ; Epithelium, Corneal/ultrastructure ; Eye Proteins/genetics ; Eye Proteins/metabolism ; Fluorescent Antibody Technique, Indirect ; Gene Expression Regulation/physiology ; Humans ; Latanoprost/pharmacokinetics ; Microscopy, Electron, Transmission ; Models, Biological ; Ophthalmic Solutions ; Real-Time Polymerase Chain Reaction
Chemical Substances	Antihypertensive Agents ; Eye Proteins ; Ophthalmic Solutions ; Latanoprost (6Z5B6HVF6O) ; Bimatoprost (QXS94885MZ)
Language	English
Publishing date	2018-08-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	391794-0
ISSN	1552-5783 ; 0146-0404
ISSN (online)	1552-5783
ISSN	0146-0404
DOI	10.1167/iovs.18-23944
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Article: Eye irritation test (eit) for hazard identification of eye irritating chemicals using reconstructed human cornea-like epithelial (rhce) tissue model

Kaluzhny, Yulia / Kandárová, Helena / d’Argembeau-Thornton, Laurence / Kearney, Paul / Klausner, Mitchell

Journal of visualized experiments. 2015 Aug. 23, , no. 102

2015

Abstract: To comply with the Seventh Amendment to the EU Cosmetics Directive and EU REACH legislation, validated non-animal alternative methods for reliable and accurate assessment of ocular toxicity in man are needed. To address this need, we have developed an ... ...

Abstract	To comply with the Seventh Amendment to the EU Cosmetics Directive and EU REACH legislation, validated non-animal alternative methods for reliable and accurate assessment of ocular toxicity in man are needed. To address this need, we have developed an eye irritation test (EIT) which utilizes a three dimensional reconstructed human cornea-like epithelial (RhCE) tissue model that is based on normal human cells. The EIT is able to separate ocular irritants and corrosives (GHS Categories 1 and 2 combined) and those that do not require labeling (GHS No Category). The test utilizes two separate protocols, one designed for liquid chemicals and a second, similar protocol for solid test articles. The EIT prediction model uses a single exposure period (30 min for liquids, 6 hr for solids) and a single tissue viability cut-off (60.0% as determined by the MTT assay). Based on the results for 83 chemicals (44 liquids and 39 solids) EIT achieved 95.5/68.2/ and 81.8% sensitivity/specificity and accuracy (SS&A) for liquids, 100.0/68.4/ and 84.6% SS&A for solids, and 97.6/68.3/ and 83.1% for overall SS&A. The EIT will contribute significantly to classifying the ocular irritation potential of a wide range of liquid and solid chemicals without the use of animals to meet regulatory testing requirements. The EpiOcular EIT method was implemented in 2015 into the OECD Test Guidelines as TG 492.
Keywords	European Union ; cosmetics ; epithelium ; exposure duration ; eyes ; guidelines ; hazard identification ; humans ; laws and regulations ; liquids ; models ; toxicity ; toxicity testing ; viability
Language	English
Dates of publication	2015-0823
Size	p. e52979.
Publishing place	Journal of Visualized Experiments
Document type	Article
ZDB-ID	2259946-0
ISSN	1940-087X
ISSN	1940-087X
DOI	10.3791/52979
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Eye Irritation Test (EIT) for Hazard Identification of Eye Irritating Chemicals using Reconstructed Human Cornea-like Epithelial (RhCE) Tissue Model.

Kaluzhny, Yulia / Kandárová, Helena / d'Argembeau-Thornton, Laurence / Kearney, Paul / Klausner, Mitchell

Journal of visualized experiments : JoVE

2015 , Issue 102, Page(s) e52979

Abstract	To comply with the Seventh Amendment to the EU Cosmetics Directive and EU REACH legislation, validated non-animal alternative methods for reliable and accurate assessment of ocular toxicity in man are needed. To address this need, we have developed an eye irritation test (EIT) which utilizes a three dimensional reconstructed human cornea-like epithelial (RhCE) tissue model that is based on normal human cells. The EIT is able to separate ocular irritants and corrosives (GHS Categories 1 and 2 combined) and those that do not require labeling (GHS No Category). The test utilizes two separate protocols, one designed for liquid chemicals and a second, similar protocol for solid test articles. The EIT prediction model uses a single exposure period (30 min for liquids, 6 hr for solids) and a single tissue viability cut-off (60.0% as determined by the MTT assay). Based on the results for 83 chemicals (44 liquids and 39 solids) EIT achieved 95.5/68.2/ and 81.8% sensitivity/specificity and accuracy (SS&A) for liquids, 100.0/68.4/ and 84.6% SS&A for solids, and 97.6/68.3/ and 83.1% for overall SS&A. The EIT will contribute significantly to classifying the ocular irritation potential of a wide range of liquid and solid chemicals without the use of animals to meet regulatory testing requirements. The EpiOcular EIT method was implemented in 2015 into the OECD Test Guidelines as TG 492.
MeSH term(s)	Animal Testing Alternatives/methods ; Cornea/drug effects ; Epithelium/drug effects ; Hazardous Substances/classification ; Hazardous Substances/toxicity ; Humans ; Irritants/classification ; Irritants/toxicity ; Tissue Engineering/methods ; Toxicity Tests/methods
Chemical Substances	Hazardous Substances ; Irritants
Language	English
Publishing date	2015-08-23
Publishing country	United States
Document type	Journal Article ; Video-Audio Media
ISSN	1940-087X
ISSN (online)	1940-087X
DOI	10.3791/52979
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Article: Role of apoptotic processes in platelet biogenesis.

Kaluzhny, Yulia / Ravid, Katya

Acta haematologica

2004 Volume 111, Issue 1-2, Page(s) 67–77

Abstract: Platelets are anucleate cells that fragment from mature megakaryocytes and play an essential role in thrombosis and hemostasis. Platelets are among the first cell types to be recruited to an injured blood vessel, assisting in endothelial repair. Platelet ...

Abstract	Platelets are anucleate cells that fragment from mature megakaryocytes and play an essential role in thrombosis and hemostasis. Platelets are among the first cell types to be recruited to an injured blood vessel, assisting in endothelial repair. Platelet hyperactivation contributes to the development of atherosclerosis, myocardial infarction, and ischemia of peripheral limbs. A fall in platelet counts, due to a variety of conditions, including disseminated intravascular coagulation, chemotherapy or genetic disorders, may lead, in most severe cases, to death from hemorrhage. This review focuses on the late stages of megakaryocyte differentiation and platelet fragmentation, including associated cytoskeletal changes, and on the importance of apoptotic events for these processes. Studies point to a unique biological system in which programmed cell death may be linked with biogenesis of new cells.
MeSH term(s)	Animals ; Apoptosis/physiology ; Blood Platelets/cytology ; Blood Platelets/physiology ; Humans ; Megakaryocytes/cytology ; Megakaryocytes/physiology
Language	English
Publishing date	2004
Publishing country	Switzerland
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S. ; Review
ZDB-ID	80008-9
ISSN	1421-9662 ; 0001-5792
ISSN (online)	1421-9662
ISSN	0001-5792
DOI	10.1159/000074487
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