Majlinda Lako - Academia.edu (original) (raw)
Papers by Majlinda Lako
Journal of cell science, Jan 15, 2002
Skin and hair follicle stem cell biology is the focus of increasing interest, not least because t... more Skin and hair follicle stem cell biology is the focus of increasing interest, not least because the adult hair follicle has well defined dermal and epithelial populations that display distinct developmental properties. Recent evidence suggests that a number of adult cell populations have much broader stem cell capabilities than previously thought. To examine whether this applied to the hair follicle, and with a view to developing the follicle as a stem cell model system we investigated whether adult hair follicles were capable of demonstrating haematopoietic stem cell activity. To investigate haematopoietic activity in hair follicles we first used in vitro haematopoietic colony assays. This demonstrated that rodent hair follicle end bulbs as well as micro-dissected dermal papilla and dermal sheath cells actively produced cells of erythroid and myeloid lineages but that follicle epithelial cells did not. As a more stringent test, we then transplanted cultured dermal papilla or dermal...
Stem cells (Dayton, Ohio), 2015
We and others have previously demonstrated that retinal cells can be derived from human embryonic... more We and others have previously demonstrated that retinal cells can be derived from human embryonic stem cells (hESC) and induced pluripotent stem cells (hiPSC) under defined culture conditions. Whilst both cell types can give rise to retinal derivatives in the absence of inductive cues, this requires extended culture periods and gives lower overall yield. Further understanding of this innate differentiation ability, the identification of key factors that drive the differentiation process and the development of clinically compatible culture conditions to reproducibly generate functional neural retina is an important goal for clinical cell based therapies. We now report that insulin-like growth factor 1 (IGF-1) can orchestrate the formation of three dimensional ocular-like structures from hESCs which, in addition to retinal pigmented epithelium and neural retina, also contain primitive lens and corneal-like structures. Inhibition of IGF-1 receptor signalling significantly reduces the f...
Stem Cells, 2008
Activation of Hox gene clusters is an early event in embryonic development since individual membe... more Activation of Hox gene clusters is an early event in embryonic development since individual members play important roles in patterning of the body axis. Their functions require precise control of spatiotemporal expression to provide positional information for the cells of the developing embryo, and the manner by which this control is achieved has generated considerable interest. The situation is different in pluripotent cells, where HOX genes are not expressed but are held in potentio as bivalent chromatin domains, which are resolved upon differentiation to permit HOX cluster activation. In this study we have used differentiation of the pluripotent embryonal carcinoma cell line NTera2SP12 and the human embryonic stem cell line H9 to examine epigenetic changes that accompany activation of the HOXA cluster and show that specific genomic loci are marked by lysine methylation of histone H3 (H3K4 tri- and dimethyl, H3K9 trimethyl) and acetylation of histone H4 even in the undifferentiated cells. The precise locations of such modified histones may be involved in controlling the colinear expression of genes from the cluster.Disclosure of potential conflicts of interest is found at the end of this article.
BioMed Research International, 2014
Stem cells are undifferentiated cells that are present in the embryonic, fetal, and adult stages ... more Stem cells are undifferentiated cells that are present in the embryonic, fetal, and adult stages of life and give rise to differentiated cells that make up the building blocks of tissue and organs. Due to their unlimited source and high differentiation potential, stem cells are considered as potentially new therapeutic agents for the treatment of infertility. Stem cells could be stimulated in vitro to develop various numbers of specialized cells including male and female gametes suggesting their potential use in reproductive medicine. During past few years a considerable progress in the derivation of male germ cells from pluripotent stem cells has been made. In addition, stem cell-based strategies for ovarian regeneration and oocyte production have been proposed as future clinical therapies for treating infertility in women. In this review, we summarized current knowledge and present future perspectives and challenges regarding the use of stem cells in reproductive medicine.
Blood, 2014
In this issue of Blood, Ramos-Mejía et al provide compelling evidence for HOXA9 as a key factor t... more In this issue of Blood, Ramos-Mejía et al provide compelling evidence for HOXA9 as a key factor that can enhance and accelerate the differentiation of these cells to blood progenitor cells in vitro.
Regenerative Medicine, 2006
The epithelium covering the cornea at the front of the eye is maintained by stem cells located at... more The epithelium covering the cornea at the front of the eye is maintained by stem cells located at its periphery, in a region known as the limbus. A lack or dysfunction of these so-called limbal stem cells (LSCs) results in the painful and blinding disease of LSC deficiency. In this review, current knowledge regarding the biology of these particular stem cells will be outlined, including recent advances that are enabling the gene expression analysis of these cells. The use of LSCs in therapeutic interventions for LSC deficiency will also be discussed, including the role for ex vivo expansion. In particular, the translation of basic science advances in LSC biology into therapeutic strategies will be highlighted.
Visual Neuroscience, 2014
Stem Cells and Development, 2009
This article, &am... more This article, "In Vitro Derivation of Human Sperm from Embryonic Stem Cells," is being retracted from Stem Cells and Development. Further details will follow online, and in a subsequent issue of the Journal.
Stem Cells, 2005
The homeobox transcription factor Nanog has been proposed to play a crucial role in the maintenan... more The homeobox transcription factor Nanog has been proposed to play a crucial role in the maintenance of the undifferentiated state of murine embryonic stem cells. A human counterpart, NANOG, has been identified, but its function and localization have not hitherto been described. We have used a combination of RNA interference and quantitative realtime polymerase chain reaction to study NANOG in human embryonic stem and embryonic carcinoma cells. Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCGbeta. Immunostaining of preimplantation human embryos showed that NANOG was expressed in the inner cell mass of expanded blastocysts but not in earlier-stage embryos, consistent with a role in the maintenance of pluripotency. Taken together, our findings suggest that NANOG acts as a gatekeeper of pluripotency in human embryonic stem and carcinoma cells by preventing their differentiation to extraembryonic endoderm and trophectoderm lineages. Stem Cells
Stem Cells, 2009
Untreatable hereditary macular dystrophy (HMD) presents a major burden to society in terms of the... more Untreatable hereditary macular dystrophy (HMD) presents a major burden to society in terms of the resulting patient disability and the cost to the healthcare provision system. HMD results in central vision loss in humans sufficiently severe for blind registration, and key issues in the development of therapeutic strategies to target these conditions are greater understanding of the causes of photoreceptor loss and the development of restorative procedures.
Mechanisms of Development, 2001
The ®rst haematopoietic stem cells in mammalian and non-mammalian vertebrates are derived from me... more The ®rst haematopoietic stem cells in mammalian and non-mammalian vertebrates are derived from mesoderm, therefore genes that are important in mesoderm patterning and formation might also play an essential role in haematopoietic stem cell commitment and differentiation. Several members of the Wnt gene family are expressed in very speci®c patterns in embryonic mesoderm and have previously been shown to act as haematopoietic growth factors. In order to investigate in detail the role that such secreted proteins play in the biology of early haematopoietic commitment we have used in vitro differentiation of murine embryonal stem (ES) as a model system. Using reversetranscriptase polymerase chain reaction analysis we identi®ed several candidate Wnt genes whose expression pattern was consistent with a role in generation, maintenance and/or differentiation of early haematopoietic progenitor cells including three genes previously shown to have a role in haematopoiesis (Wnt5a, Wnt2b and Wnt10b). The most interesting candidate was Wnt3, because of its strong and regulated expression during in vitro differentiation of murine ES cells as well as its early embryonic expression in mesoderm. Overexpression of Wnt3 was suf®cient to cause a consistent increase in the number of embryoid bodies committing to haematopoiesis further strengthening the evidence that this protein can enhance haematopoietic commitment during in vitro differentiation of ES cells. In addition, overexpression of Wnt3 caused a marked upregulation of Brachyury expression, thus providing some evidence that Brachyury may be one of the target genes for the Wnt3 signalling pathway. q
STEM CELLS, 2000
The corneal epithelium is maintained by a population of stem cells known as limbal stem cells [LS... more The corneal epithelium is maintained by a population of stem cells known as limbal stem cells [LSCs] due to their location in the basal layer of the outer border of the cornea known as the limbus. Treatment of limbal stem cell deficiency [LSCD] has been achieved with transplantation of ex vivo expanded LSCs taken from a small biopsy of limbus. This is a relatively new technique and as such, specific national or international guidance has yet to be established. Due to the lack of such specific guidance, our group has sought to minimise any risk to the patient by adopting certain modifications to the research methodologies in use at present. These include the replacement of all non-human animal products from the culture system and the production of all reagents and cultures under Good Manufacturing Practice [GMP] conditions. In addition, for the first time, a strictly defined uniform group of patients with total unilateral LSCD and no other significant ocular conditions has been used to allow the success or failure of treating LSCD to be attributable directly to the proposed stem cell therapy.
Journal of cell science, Jan 15, 2002
Skin and hair follicle stem cell biology is the focus of increasing interest, not least because t... more Skin and hair follicle stem cell biology is the focus of increasing interest, not least because the adult hair follicle has well defined dermal and epithelial populations that display distinct developmental properties. Recent evidence suggests that a number of adult cell populations have much broader stem cell capabilities than previously thought. To examine whether this applied to the hair follicle, and with a view to developing the follicle as a stem cell model system we investigated whether adult hair follicles were capable of demonstrating haematopoietic stem cell activity. To investigate haematopoietic activity in hair follicles we first used in vitro haematopoietic colony assays. This demonstrated that rodent hair follicle end bulbs as well as micro-dissected dermal papilla and dermal sheath cells actively produced cells of erythroid and myeloid lineages but that follicle epithelial cells did not. As a more stringent test, we then transplanted cultured dermal papilla or dermal...
Stem cells (Dayton, Ohio), 2015
We and others have previously demonstrated that retinal cells can be derived from human embryonic... more We and others have previously demonstrated that retinal cells can be derived from human embryonic stem cells (hESC) and induced pluripotent stem cells (hiPSC) under defined culture conditions. Whilst both cell types can give rise to retinal derivatives in the absence of inductive cues, this requires extended culture periods and gives lower overall yield. Further understanding of this innate differentiation ability, the identification of key factors that drive the differentiation process and the development of clinically compatible culture conditions to reproducibly generate functional neural retina is an important goal for clinical cell based therapies. We now report that insulin-like growth factor 1 (IGF-1) can orchestrate the formation of three dimensional ocular-like structures from hESCs which, in addition to retinal pigmented epithelium and neural retina, also contain primitive lens and corneal-like structures. Inhibition of IGF-1 receptor signalling significantly reduces the f...
Stem Cells, 2008
Activation of Hox gene clusters is an early event in embryonic development since individual membe... more Activation of Hox gene clusters is an early event in embryonic development since individual members play important roles in patterning of the body axis. Their functions require precise control of spatiotemporal expression to provide positional information for the cells of the developing embryo, and the manner by which this control is achieved has generated considerable interest. The situation is different in pluripotent cells, where HOX genes are not expressed but are held in potentio as bivalent chromatin domains, which are resolved upon differentiation to permit HOX cluster activation. In this study we have used differentiation of the pluripotent embryonal carcinoma cell line NTera2SP12 and the human embryonic stem cell line H9 to examine epigenetic changes that accompany activation of the HOXA cluster and show that specific genomic loci are marked by lysine methylation of histone H3 (H3K4 tri- and dimethyl, H3K9 trimethyl) and acetylation of histone H4 even in the undifferentiated cells. The precise locations of such modified histones may be involved in controlling the colinear expression of genes from the cluster.Disclosure of potential conflicts of interest is found at the end of this article.
BioMed Research International, 2014
Stem cells are undifferentiated cells that are present in the embryonic, fetal, and adult stages ... more Stem cells are undifferentiated cells that are present in the embryonic, fetal, and adult stages of life and give rise to differentiated cells that make up the building blocks of tissue and organs. Due to their unlimited source and high differentiation potential, stem cells are considered as potentially new therapeutic agents for the treatment of infertility. Stem cells could be stimulated in vitro to develop various numbers of specialized cells including male and female gametes suggesting their potential use in reproductive medicine. During past few years a considerable progress in the derivation of male germ cells from pluripotent stem cells has been made. In addition, stem cell-based strategies for ovarian regeneration and oocyte production have been proposed as future clinical therapies for treating infertility in women. In this review, we summarized current knowledge and present future perspectives and challenges regarding the use of stem cells in reproductive medicine.
Blood, 2014
In this issue of Blood, Ramos-Mejía et al provide compelling evidence for HOXA9 as a key factor t... more In this issue of Blood, Ramos-Mejía et al provide compelling evidence for HOXA9 as a key factor that can enhance and accelerate the differentiation of these cells to blood progenitor cells in vitro.
Regenerative Medicine, 2006
The epithelium covering the cornea at the front of the eye is maintained by stem cells located at... more The epithelium covering the cornea at the front of the eye is maintained by stem cells located at its periphery, in a region known as the limbus. A lack or dysfunction of these so-called limbal stem cells (LSCs) results in the painful and blinding disease of LSC deficiency. In this review, current knowledge regarding the biology of these particular stem cells will be outlined, including recent advances that are enabling the gene expression analysis of these cells. The use of LSCs in therapeutic interventions for LSC deficiency will also be discussed, including the role for ex vivo expansion. In particular, the translation of basic science advances in LSC biology into therapeutic strategies will be highlighted.
Visual Neuroscience, 2014
Stem Cells and Development, 2009
This article, &am... more This article, "In Vitro Derivation of Human Sperm from Embryonic Stem Cells," is being retracted from Stem Cells and Development. Further details will follow online, and in a subsequent issue of the Journal.
Stem Cells, 2005
The homeobox transcription factor Nanog has been proposed to play a crucial role in the maintenan... more The homeobox transcription factor Nanog has been proposed to play a crucial role in the maintenance of the undifferentiated state of murine embryonic stem cells. A human counterpart, NANOG, has been identified, but its function and localization have not hitherto been described. We have used a combination of RNA interference and quantitative realtime polymerase chain reaction to study NANOG in human embryonic stem and embryonic carcinoma cells. Transfection of NANOG-specific small interfering RNAs reduced levels of NANOG transcript and protein and induced activation of the extraembryonic endoderm-associated genes GATA4, GATA6, LAMININ B1, and AFP as well as upregulation of trophectoderm-associated genes CDX2, GATA2, hCG-alpha, and hCGbeta. Immunostaining of preimplantation human embryos showed that NANOG was expressed in the inner cell mass of expanded blastocysts but not in earlier-stage embryos, consistent with a role in the maintenance of pluripotency. Taken together, our findings suggest that NANOG acts as a gatekeeper of pluripotency in human embryonic stem and carcinoma cells by preventing their differentiation to extraembryonic endoderm and trophectoderm lineages. Stem Cells
Stem Cells, 2009
Untreatable hereditary macular dystrophy (HMD) presents a major burden to society in terms of the... more Untreatable hereditary macular dystrophy (HMD) presents a major burden to society in terms of the resulting patient disability and the cost to the healthcare provision system. HMD results in central vision loss in humans sufficiently severe for blind registration, and key issues in the development of therapeutic strategies to target these conditions are greater understanding of the causes of photoreceptor loss and the development of restorative procedures.
Mechanisms of Development, 2001
The ®rst haematopoietic stem cells in mammalian and non-mammalian vertebrates are derived from me... more The ®rst haematopoietic stem cells in mammalian and non-mammalian vertebrates are derived from mesoderm, therefore genes that are important in mesoderm patterning and formation might also play an essential role in haematopoietic stem cell commitment and differentiation. Several members of the Wnt gene family are expressed in very speci®c patterns in embryonic mesoderm and have previously been shown to act as haematopoietic growth factors. In order to investigate in detail the role that such secreted proteins play in the biology of early haematopoietic commitment we have used in vitro differentiation of murine embryonal stem (ES) as a model system. Using reversetranscriptase polymerase chain reaction analysis we identi®ed several candidate Wnt genes whose expression pattern was consistent with a role in generation, maintenance and/or differentiation of early haematopoietic progenitor cells including three genes previously shown to have a role in haematopoiesis (Wnt5a, Wnt2b and Wnt10b). The most interesting candidate was Wnt3, because of its strong and regulated expression during in vitro differentiation of murine ES cells as well as its early embryonic expression in mesoderm. Overexpression of Wnt3 was suf®cient to cause a consistent increase in the number of embryoid bodies committing to haematopoiesis further strengthening the evidence that this protein can enhance haematopoietic commitment during in vitro differentiation of ES cells. In addition, overexpression of Wnt3 caused a marked upregulation of Brachyury expression, thus providing some evidence that Brachyury may be one of the target genes for the Wnt3 signalling pathway. q
STEM CELLS, 2000
The corneal epithelium is maintained by a population of stem cells known as limbal stem cells [LS... more The corneal epithelium is maintained by a population of stem cells known as limbal stem cells [LSCs] due to their location in the basal layer of the outer border of the cornea known as the limbus. Treatment of limbal stem cell deficiency [LSCD] has been achieved with transplantation of ex vivo expanded LSCs taken from a small biopsy of limbus. This is a relatively new technique and as such, specific national or international guidance has yet to be established. Due to the lack of such specific guidance, our group has sought to minimise any risk to the patient by adopting certain modifications to the research methodologies in use at present. These include the replacement of all non-human animal products from the culture system and the production of all reagents and cultures under Good Manufacturing Practice [GMP] conditions. In addition, for the first time, a strictly defined uniform group of patients with total unilateral LSCD and no other significant ocular conditions has been used to allow the success or failure of treating LSCD to be attributable directly to the proposed stem cell therapy.