[Definitions of key words in stem cell biology].
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Developmental potentials of hematopoietic and neural stem cells following injection into pre-implantation blastocysts.
Pluripotent embryonic stem (ES) cells are able to differentiate in vivo into all cell types of the fetal and adult organism and in vitro they can differentiate into a variety of cell types. In contrast, multipotent somatic stem cells (SSCs) isolated from fetal and adult tissues differentiate into mature effector cells of their tissue. However, recent studies imply that SSCs can also generate cell types of heterologous tissues indicating unexpected broad differentiation potentials. In order to examine and compare the developmental potentials of SSCs, we exposed hematopoietic stem cells (HSCs) and neural stem cells (NSCs) to an environment that is permissive for the development of all cell types of the embryo, namely the mouse preimplantation blastocyst. Using this approach we were able to detect progeny of HSCs and NSCs frequently in developing chimeric animals. Analysis of 18 different adult tissues revealed minor preferences of HSCs for hematopoietic tissues, while progeny of NSCs were mostly detected in neural tissues. Furthermore we observe that human cord blood-derived CD34+ and CD34+/CD38- HSCs also engraft murine embryos and that human donor contribution persists into adulthood. Our studies show the existence of tissue specific engraftment preferences of HSCs and NSCs and that both stem cell types are non-ES cell-like.
ADP-ribosyl Cyclase↗
Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration.
The subventricular zone (SVZ) is a principal source of adult neural stem cells in the rodent brain, generating thousands of olfactory bulb neurons every day. If the adult human brain contains a comparable germinal region, this could have considerable implications for future neuroregenerative therapy. Stem cells have been isolated from the human brain, but the identity, organization and function of adult neural stem cells in the human SVZ are unknown. Here we describe a ribbon of SVZ astrocytes lining the lateral ventricles of the adult human brain that proliferate in vivo and behave as multipotent progenitor cells in vitro. This astrocytic ribbon has not been observed in other vertebrates studied. Unexpectedly, we find no evidence of chains of migrating neuroblasts in the SVZ or in the pathway to the olfactory bulb. Our work identifies SVZ astrocytes as neural stem cells in a niche of unique organization in the adult human brain.
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[A stem cell therapy for stroke].
It has been reported that the adult mammalian harbors stem cells or progenitors that retain the potential for both neural production and differentiation. Recently, several progenitors derived from non-neural samples as well as the neural tissues in humans are thought to be a good candidate for the regenerative medicine. Multipotent embryonic stem cells prepared from the fertilized egg or neural stem cells from fetus may be used as allotransplants. Progenitors derived from adult brain, bone marrow, code blood, or lipid can be used as autotransplants. Bone marrow in adult mammals contains several types of precursor and stem cells such as hematopoietic stem cells, non-hematopoietic stem cells, and other unknown precursor cells. The distinct population of progenitor cells in the bone marrow are thought to retain the potential for both neural production and differentiation, and may contribute to a therapeutic strategy for stroke. In the present report, the possible therapeutic strategy of the stem cell transplantation for the stroke is discussed.
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Lineage promiscuity and plasticity in hematopoietic development.
Hematopoiesis has provided a valuable model for understanding how genetic programs are established to decide cell fates in multipotent stem or progenitor cells. The identification of common myeloid and lymphoid progenitors has allowed us to directly assess the regulatory mechanisms of lineage commitment. Multiple genes of hematopoietic lineages, including transcription factors, are coexpressed in hematopoietic stem cells and progenitors, a phenomenon referred to as "lineage priming." The accessibility for multiple transcription factors promiscuously allows flexibility in cell fate commitments at the multipotent stages. The changes in the expression levels and timing of transcription factors can induce lineage conversion of committed cells, indicating that the regulation of transcription factors might be primarily critical for maintaining hierarchical hematopoietic development.
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Immunophenotype of human adipose-derived cells: temporal changes in stromal-associated and stem cell-associated markers.
Adipose tissue represents an abundant and accessible source of multipotent adult stem cells and is used by many investigators for tissue engineering applications; however, not all laboratories use cells at equivalent stages of isolation and passage. We have compared the immunophenotype of freshly isolated human adipose tissue-derived stromal vascular fraction (SVF) cells relative to serial-passaged adipose-derived stem cells (ASCs). The initial SVF cells contained colony-forming unit fibroblasts at a frequency of 1:32. Colony-forming unit adipocytes and osteoblasts were present in the SVF cells at comparable frequencies (1:28 and 1:16, respectively). The immunophenotype of the adipose-derived cells based on flow cytometry changed progressively with adherence and passage. Stromal cell-associated markers (CD13, CD29, CD44, CD63, CD73, CD90, CD166) were initially low on SVF cells and increased significantly with successive passages. The stem cell-associated marker CD34 was at peak levels in the SVF cells and/or early-passage ASCs and remained present, although at reduced levels, throughout the culture period. Aldehyde dehydrogenase and the multidrug-resistance transport protein (ABCG2), both of which have been used to identify and characterize hematopoietic stem cells, are expressed by SVF cells and ASCs at detectable levels. Endothelial cell-associated markers (CD31, CD144 or VE-cadherin, vascular endothelial growth factor receptor 2, von Willebrand factor) were expressed on SVF cells and did not change significantly with serial passage. Thus, the adherence to plastic and subsequent expansion of human adipose-derived cells in fetal bovine serum-supplemented medium selects for a relatively homogeneous cell population, enriching for cells expressing a stromal immunophenotype, compared with the heterogeneity of the crude SVF.
Adipose Tissue↗
Bone morphogenetic protein-2 induces differentiation of multipotent C3H10T1/2 cells into osteoblasts, chondrocytes, and adipocytes in vivo and in vitro.
Mesenchymal stem cells capable of differentiating into multiple cell types are potentially useful therapeutically for regeneration of bone and cartilaginous tissues. Multipotent fibroblastic C3H10T1/2 cells are known to differentiate into osteoblasts, chondrocytes, and adipocytes in response to certain growth factors. In this study we compared the effects of bone morphogenetic protein (BMP)-2 on the differentiation of C3H10T1/2 and MC3T3-E1 preosteoblastic cells. Incubation of these cells with BMP-2 resulted in a dose- and time-dependent increase in alkaline phosphatase activity, but the increase in MC3T3-E1 cells was much higher than that in C3H10T1/2 cells. BMP-2 also induced differentiation of C3H10T1/2 cells but not MC3T3-E1 cells into chondrocytes and adipocytes. Reverse transcription-polymerase chain reaction analysis showed that these commitments were accompanied by the specific expression of osteocalcin, aggrecan, and PPARgamma. To investigate the in vivo differential property, these cells were inoculated with BMP-2 in a diffusion chamber and transplanted into the mouse peritoneal cavity for 4 weeks. The transplanted C3H10T1/2 cells formed mineralized bone containing chondrocytes and adipocytes, whereas MC3T3-E1 created only bony tissue. Our results indicate that BMP-2 can induce the differentiation of C3H10T1/2 into osteoblasts, chondrocytes, and adipocytes in both in vivo and in vitro conditions, and that C3H10T1/2 could be used to examine the BMP-2-induced regulatory mechanisms of mesenchymal differentiation.
Aggrecans↗
The specific enhancement of interferon alpha induced growth inhibition by BCR/ABL only occurs in multipotent cells.
INTRODUCTION: The causative oncogene in CML is the BCR/ABL protein tyrosine kinase. This stem cell disease is often treated with interferon alpha (IFN-alpha) which can initiate haematological and cytological remission which is associated with increased survival. There is however no clear indication of why CML cells are more responsive to IFN-alpha. MATERIALS AND METHODS: To establish if BCR/ABL increases the sensitivity of multipotent cells to IFN-alpha a temperature sensitive mutant of BCR/ABL was expressed in the multipotent haemopoietic stem cell line FDCP-Mix. The effect of IFN-alpha in terms of proliferation, induction of apoptosis, changes in cell cycle inhibitor proteins, and differentiation was assessed by [3H]thymidine incorporation, Annexin V and Western blot analysis. RESULTS: When the BCR/ABL tyrosine kinase was activated, the IFN-alpha-induced inhibition on the growth rate of the FDCP-Mix cell population was more marked than in control populations. The BCR/ABL-mediated effect was due to decreased rates of DNA synthesis. There was no IFN-alpha-mediated induction of apoptosis. This enhanced BCR/ABL mediated growth inhibition occurred over a range of growth factor concentrations and was independent of changes in p21(Cip1) and p27(Kip) levels. When FDCP-Mix cells were induced to differentiate into mature macrophages and neutrophils in the presence of IFN-alpha, there was increased sensitivity to IFN-alpha that was independent of BCR/ABL activity. CONCLUSION: BCR/ABL PTK expression in this primitive multipotent haematopoietic cell line results in an enhanced response to IFN-alpha. In contrast, the more mature myeloid progenitor cells are equally responsive to this growth inhibitor. This data may explain some of the clinical effects of IFN-alpha.
Apoptosis↗
[Neural stem cell, as a source of graft material for transplantation in neuronal disease].
Self-renewing and multipotent neural stem cells are present in the adult human brain. We successfully harvested neural stem cells from mice and humans using misexpressed EGFP proteins under the control of the nestin second intron enhancer. High-level EGFP expressors derived from mouse embryos included a distinct subpopulation of cells that were self-renewable and multipotent. Further, we obtained that neural progenitor cells from rat fetal spinal cords using a neurosphere technique, and demonstrated their ability to divide and differentiate into neurons in vivo, where they were integrated into the host tissue in the injured rat spinal cord with resultant behavioral improvement of the recipient rat. We also harvested tyrosine hydroxylase-positive neurons from a transgenic mouse expressing GFP under the control of the tyrosine hydroxylase promoter, and successfully transplanted them into the striatum of rats with parkinsonism with marked improvement of the neurological symptoms. Since neural stem cells can adapt well in the host CNS, studies should focus on their application as a vector in gene therapy and on the introduction in vivo or ex vivo of genes to control their proliferation and differentiation. Neural stem cells are a potential, useful source for developing new therapy for CNS disorders.
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Time of transplantation and cell preparation determine neural stem cell survival in a mouse model of Huntington's disease.
Cell replacement therapies for neurodegenerative diseases, using multipotent neural stem cells (NSCs), require above all, a good survival of the graft. In this study, we unilaterally injected quinolinic acid (QA) into the striatum of adult mice and transplanted syngeneic NSCs of enhanced green fluorescent protein-transgenic mice into the lesioned striatum. The injection of QA leads to an excitotoxic lesion with selective cell death of the medium sized spiny neurons, the same cells that are affected in Huntington's disease. In order to investigate the best timing of transplantation for the survival of donor cells, we transplanted the stem cells at 2, 7 and 14 days after injury. In addition, the influence of graft preparation prior to transplantation, i.e., intact neurospheres versus dissociated cell suspension on graft survival was investigated. By far the best survival was found with the combination of early transplantation (i.e., 2 days after QA-lesion) with the use of neurospheres instead of dissociated cell suspension. This might be due to the different states of host's astrocytic and microglia activation which we found to be moderate at 2, but pronounced at 7 and 14 days after QA-lesion. We also investigated brain derived neurotrophic factor (BDNF)-expression in the striatum after QA-lesion and found no significant change in BDNF protein-level. We conclude that already the method of graft preparation of NSCs for transplantation, as well as the timing of the transplantation procedure strongly affects the survival of the donor cells when grafted into the QA-lesioned striatum of adult mice.
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Adult neurogenesis in the mammalian central nervous system: functionality and potential clinical interest.
In the past decades, much evidence has confirmed that neurogenesis occurs in the adult brain and that neural stem cells reside in the adult central nervous system, overturning the long-held dogma that we are born with a certain number of nerve cells and that the brain cannot generate new neurons and renew itself. In the adult brain, neurogenesis occurs mainly in two areas: the hippocampus and the subventricular zone, and self-renewing, multipotent neural stem cells have been isolated and characterized in vitro from various regions of the adult central nervous system. Though significant advances have been made in this field of research, the identification and function of neural stem cells in the adult central nervous system remain the source of debate and controversy. Neurogenesis is modulated by several normal and pathologic conditions, suggesting the involvement of the hippocampus and the subventricular zone in a broad range of functions, and that environmental stimuli and pathological conditions may have long-term consequences on the architecture and functioning of the central nervous system. Neurogenesis is involved in processes such as learning, memory, and depression, and may also be involved in regenerative attempts after injuries to the central nervous system. However, the contribution of neurogenesis to these phenomena remains to be elucidated. Neural stem cells also hold the promise to cure a broad range of neurological diseases and injuries. Cell therapeutic interventions may involve both cell transplantation and the stimulation of endogenous neural progenitor cells.
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Extracellular nucleotide signaling in adult neural stem cells: synergism with growth factor-mediated cellular proliferation.
We have previously shown that the extracellular nucleoside triphosphate-hydrolyzing enzyme NTPDase2 is highly expressed in situ by stem/progenitor cells of the two neurogenic regions of the adult murine brain: the subventricular zone (type B cells) and the dentate gyrus of the hippocampus (residual radial glia). We explored the possibility that adult multipotent neural stem cells express nucleotide receptors and investigated their functional properties in vitro. Neurospheres cultured from the adult mouse SVZ in the presence of epidermal growth factor and fibroblast growth factor 2 expressed the ecto-nucleotidases NTPDase2 and the tissue non-specific isoform of alkaline phosphatase, hydrolyzing extracellular ATP to adenosine. ATP, ADP and, to a lesser extent, UTP evoked rapid Ca(2+) transients in neurospheres that were exclusively mediated by the metabotropic P2Y(1) and P2Y(2) nucleotide receptors. In addition, agonists of these receptors and low concentrations of adenosine augmented cell proliferation in the presence of growth factors. Neurosphere cell proliferation was attenuated after application of the P2Y(1)-receptor antagonist MRS2179 and in neurospheres from P2Y(1)-receptor knockout mice. In situ hybridization identified P2Y(1)-receptor mRNA in clusters of SVZ cells. Our results infer nucleotide receptor-mediated synergism that augments growth factor-mediated cell proliferation. Together with the in situ data, this supports the notion that extracellular nucleotides contribute to the control of adult neurogenesis.
Adenosine↗
Isolation and characterization of hematopoietic progenitor cells in canine bone marrow.
For ultimate diagnoses of canine leukemia or malignant lymphoma, we sought to isolate hematopoietic progenitor cells (HPCs) from canine bone marrow (BM) using physiological phenotypes. Canine BM cells were separated by equilibrium discontinued density centrifugation, and HPCs, detected by in vitro colony formation, were significantly enriched in the relatively low density (LD) fraction. In flow cytometry, many CD34 or MHC class II expressing cells were detected in the LD fraction, but these were not significantly enriched. When the LD cells were separated, using a cell-sorting method, into cells with high affinity of wheat germ agglutinin (WGAhigh) and cells with WGAlow, almost all multipotent HPCs (MHPCs) and HPCs committed to myeloid lineage were found in the WGAhigh population. When the WGAhigh population was further stained for rhodamin 123, almost all MHPCs were included in the dull population (Rhlow), but not in the bright one (Rhhigh). Morphologically, most Rhlow cells were round, blastic cells containing a large nucleus with nucleoli and narrow cytoplasm. Based on these results, we suggest that all of the MHPCs in canine BM show the Rhlow WGAhigh LD phenotype, and may contain hematopoietic stem cells, which are the primitive HPCs.
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Hair follicle bulge: a fascinating reservoir of epithelial stem cells.
Hair follicles reconstitute themselves though the hair cycle, suggesting the presence of intrinsic stem cells. In contrast to the previous belief that stem cells reside in the bulbar region of hair follicles, stem cells were detected in the bulge area, a contiguous part of outer root sheath, that provides the insertion point for arrector pili muscle and marks the bottom of the permanent portion of hair follicles. The bulge cells are morphologically undifferentiated and slow-cycling under the normal conditions. Later, studies successively demonstrated that bulge cells possess stem cell properties such as high proliferative capacity and multipotency to regenerate not only hair follicles but also sebaceous glands and epidermis. Our knowledge of the bulge cell biology is rapidly increasing because of the identification of novel cell surface markers, the ability to isolate living bulge cells, and microarray analysis of multiple gene expression. Importantly, novel cell surface markers were identified on human bulge cells using precise laser capture microdissection and microarray analyses. Use of these markers enabled the successful enrichment of living human bulge cells, raising the possibility of future treatments of hair disorders using stem cells. Additional clinical relevance of bulge cell biology includes the importance of bulge cells as a gene therapy target and their possible roles in tumorigenesis.
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GATA-3: an unexpected regulator of cell lineage determination in skin.
Multipotent skin stem cells give rise to epidermis and its appendages, including the hair follicle. The Lef-1/Tcf family of Wnt-regulated transcription factors plays a major role in specification of the hair shaft, but little is known about how the equally important hair channel, the inner root sheath (IRS), develops in concert to shape and guide the hair. In a microarray screen to search for transcriptional regulators of hair follicle morphogenesis, we identified GATA-3, a key regulator of T-cell lineage determination. Surprisingly, this transcription factor is essential for stem cell lineage determination in skin, where it is expressed at the onset of epidermal stratification and IRS specification in follicles. GATA-3-null/lacZ knock-in embryos can survive up to embryonic day 18.5 (E18.5), when they fail to form the IRS. Skin grafting unveiled additional defects in GATA-3-null hairs and follicles. IRS progenitors failed to differentiate, whereas cortical progenitors differentiated, but produced an aberrant hair structure. Curiously, some GATA-3-null progenitor cells expressed mixed IRS and hair shaft markers. Taken together, these findings place GATA-3 with Lef-1/Wnts at the crossroads of the IRS versus hair shaft cell fate decision in hair follicle morphogenesis. This newfound function for GATA-3 in skin development strengthens the parallels between the differentiation programs governing hair follicle and lymphocyte differentiation.
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Heparan sulfates isolated from adult neural progenitor cells can direct phenotypic maturation.
Multipotent progenitor stem cells that generate both neurons and glia are components of the hippocampus, subventricular zone and olfactory system of adult mammalian nervous system. The lineage choices any stem cell makes are known to be greatly dependent on the constitution of the extracellular matrix to which they are exposed during their development. Here, the adult rat hippocampus was used as a source of cells for clonal culture in order to investigate the effects of the extracellular glycosaminoglycan heparan sulfate (HS). Neurospheres were readily generated from adult tissue and could be used as a source of cells for further experiments. HS species that promote the actions of fibroblast growth factor-2 (FGF2) for embryonic neural progenitors were found to inhibit the actions of this mitogen for adult progenitors. Only HS fractions that promoted the actions of FGF1 had mitogenic effects on these adult cells. The adult cells proved difficult to clone from single cells. However, when endogenous HS was purified from these cells and added back at high concentration to single cells, the clones were capable of generating plentiful neuronal and glial progeny. The adult hippocampal progenitor (AHP) HS is composed of 32 kDa chains bearing 3 sulfated domains. A proportion of primary osteoblast stem cells exposed to the hippocampal HS adopt neuronal phenotypes. Hence, there appears to be a combination of HS-binding extracellular molecules that predispose cells to particular lineages.
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Multipotent neural progenitor or stem-like cells may be uniquely suited for therapy for some neurodegenerative conditions.
Multipotent neural progenitors or stem cells (or cells which mimic their behavior) are capable of differentiating along multiple central nervous system (CNS) cell-type lineages, neuronal and glial. They can engraft as integral members of normal structures throughout the host CNS without disturbing other neurobiological processes. By exploiting their basic biologic properties, these cells may be able to disseminate therapeutic gene products in a sustained, direct fashion throughout the CNS. In addition, they may replace dysfunctional neurons and glia in both a site-specific and global manner. They may play a therapeutic role in neurodegenerative conditions that occur both during development and in the mature brain. The ability of neural stem cells to respond to neurogenic cues not only when they occur during their normal developmental expression but even when induced or "reactivated" at later stages following injury, may entrance their utility in reconstituting damaged CNS regions. Thus, these vehicles may overcome many of the limitations of viral and non-neural cellular vectors, as well as pharmacologic and genetic interventions. The feasibility of this broadly applicable neural stem cell-based strategy has been demonstrated in a number of murine models of neurodegenerative disease. The focus of this review will be our recent observation of a possible tropism of such cells for neurodegenerative environments.
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A role for alpha1 tubulin-expressing Müller glia in regeneration of the injured zebrafish retina.
Alpha1 tubulin (alpha1T) is a neuron-specific microtubule protein whose expression is induced in the developing and regenerating CNS. In the adult CNS, alpha1T expression remains high in neural progenitors. Transgenic zebrafish harboring a 1.7 kb alpha1T promoter fragment along with the first exon and intron express the transgene in a manner that recapitulates expression of the endogenous gene. We recently showed that this promoter mediates gene induction in retinal ganglion cells during optic nerve regeneration and in a subset of Müller glia that proliferate after retinal injury (Senut et al., 2004). To further characterize these Müller glia, we generated transgenic fish harboring an alpha1T promoter fragment that is specifically induced in these cells after retinal damage. Transgene expression, bromodeoxyuridine (BrdU) labeling, and stem cell marker expression suggested that alpha1T-expressing Müller glia dedifferentiate and become multipotent in response to injury. In addition, green fluorescent protein and BrdU-mediated lineage tracing combined with retinal gene expression analysis indicated that alpha1T-expressing Müller glia were capable of generating retinal neurons and glia. These data strongly suggest alpha1T-expressing Müller glia dedifferentiate and mediate regeneration of the injured zebrafish retina.
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