scholarly journals Haemangioma: A Study of the Biology

2021 ◽  
Author(s):  
◽  
Tinte Itinteang
Keyword(s):  
Stem Cells ◽  
Progenitor Cell ◽  
Primary Tumour ◽  
Renin Angiotensin System ◽  
Erythropoietin Receptor ◽  
Regulatory Role ◽  
Treatment Modalities ◽  
White Female ◽  
Angiotensin I

<p>Infantile haemangioma (IH), considered a primary tumour of the microvasculature, is the most common tumour of infancy affecting about 10% of Caucasian infants. IH predominantly affects white, female and premature infants. IH typically undergoes an initial rapid proliferation during infancy (proliferative phase) characterised by aggressive angiogenesis, followed by spontaneous involution over the next 1-5 years (involuting phase) and continued improvement up to 10 years (involuted phase), often with a fibro-fatty residuum. IH consists of cells of various lineages, with the presence of mesenchymal stem cells, endothelial progenitor cells, endothelial cells, myeloid haematopoietic cells, and pericytes. This thesis demonstrates the expression of primitive (stem/progenitor cell) markers on the endothelium of IH. The expression of the transcription factors brachyury, Tal-1 and GATA-2, along with the demonstration of erythropoiesis in IH explants in vitro supports the hypothesis that IH consists of a primitive endothelium similar to an embryonic haemogenic endothelium. The expression of the erythropoietin receptor and haemoglobin zeta chain by the endothelium of IH further strengthens the notion that IH is a haemogenic endothelium. Consistent with the primitive embryonic origin, the expression of the placental markers human chorionic gonadotrophin (hCG) and human placenta lactogen (hPL), but not cytokeratin 7 (CK7) or human leucocyte antigen- G (HLA-G) by the endothelium in IH, supports a placental chorionic villous mesenchymal core cell, and not a trophoblast, origin for IH. IH thus has an extraembryonically derived primitive mesodermal origin. This primitive mesoderm is able to account for the haemogenic endothelium phenotype of the endothelium of proliferating IH microvessels with its capacity for both erythropoietic and mesenchymal differentiation. Additionally, data are presented to show that IH expresses key components of the renin-angiotensin system (RAS), angiotensin converting enzyme (ACE), angiotensin II (ATII), angiotensin receptor 2 (ATR2). Cultured IH-derived stem cells can be induced to proliferate and form blast colonies in response to ATII treatment. The crucial regulatory role of RAS in the proliferation and differentiation of the stem/progenitor cell population within IH accounts for the natural progression of IH. A model is proposed to provide a rational explanation for the serendipiditous discovery of the dramatic effect that the β-blocker, Propranolol has in accelerating involution of IH. The hypothesis that Propranolol exerts its action on IH through modulation of the RAS by blocking renin activity and preventing the conversion of angiotensinogen to angiotensin I, thereby reducing ATII levels, has led to a clinical trial using Captopril, an ACE inhibitor in the treatment of problematic proliferating IH. The observed accelerated involution of IH by Captopril which blocks the conversion of angiotensin I to ATII confirms a key regulatory role for RAS in the biology of IH This discovery underpins the development of potentially safer and novel treatment modalities for this enigmatic condition.</p>

scholarly journals Haemangioma: A Study of the Biology

2021 ◽  
Author(s):  
◽  
Tinte Itinteang
Keyword(s):  
Stem Cells ◽  
Progenitor Cell ◽  
Primary Tumour ◽  
Renin Angiotensin System ◽  
Erythropoietin Receptor ◽  
Regulatory Role ◽  
Treatment Modalities ◽  
White Female ◽  
Angiotensin I

<p>Infantile haemangioma (IH), considered a primary tumour of the microvasculature, is the most common tumour of infancy affecting about 10% of Caucasian infants. IH predominantly affects white, female and premature infants. IH typically undergoes an initial rapid proliferation during infancy (proliferative phase) characterised by aggressive angiogenesis, followed by spontaneous involution over the next 1-5 years (involuting phase) and continued improvement up to 10 years (involuted phase), often with a fibro-fatty residuum. IH consists of cells of various lineages, with the presence of mesenchymal stem cells, endothelial progenitor cells, endothelial cells, myeloid haematopoietic cells, and pericytes. This thesis demonstrates the expression of primitive (stem/progenitor cell) markers on the endothelium of IH. The expression of the transcription factors brachyury, Tal-1 and GATA-2, along with the demonstration of erythropoiesis in IH explants in vitro supports the hypothesis that IH consists of a primitive endothelium similar to an embryonic haemogenic endothelium. The expression of the erythropoietin receptor and haemoglobin zeta chain by the endothelium of IH further strengthens the notion that IH is a haemogenic endothelium. Consistent with the primitive embryonic origin, the expression of the placental markers human chorionic gonadotrophin (hCG) and human placenta lactogen (hPL), but not cytokeratin 7 (CK7) or human leucocyte antigen- G (HLA-G) by the endothelium in IH, supports a placental chorionic villous mesenchymal core cell, and not a trophoblast, origin for IH. IH thus has an extraembryonically derived primitive mesodermal origin. This primitive mesoderm is able to account for the haemogenic endothelium phenotype of the endothelium of proliferating IH microvessels with its capacity for both erythropoietic and mesenchymal differentiation. Additionally, data are presented to show that IH expresses key components of the renin-angiotensin system (RAS), angiotensin converting enzyme (ACE), angiotensin II (ATII), angiotensin receptor 2 (ATR2). Cultured IH-derived stem cells can be induced to proliferate and form blast colonies in response to ATII treatment. The crucial regulatory role of RAS in the proliferation and differentiation of the stem/progenitor cell population within IH accounts for the natural progression of IH. A model is proposed to provide a rational explanation for the serendipiditous discovery of the dramatic effect that the β-blocker, Propranolol has in accelerating involution of IH. The hypothesis that Propranolol exerts its action on IH through modulation of the RAS by blocking renin activity and preventing the conversion of angiotensinogen to angiotensin I, thereby reducing ATII levels, has led to a clinical trial using Captopril, an ACE inhibitor in the treatment of problematic proliferating IH. The observed accelerated involution of IH by Captopril which blocks the conversion of angiotensin I to ATII confirms a key regulatory role for RAS in the biology of IH This discovery underpins the development of potentially safer and novel treatment modalities for this enigmatic condition.</p>

scholarly journals Stem Cells and Gene Therapy in Progressive Hearing Loss: the State of the Art

2021 ◽  
Author(s):  
Aida Nourbakhsh ◽  
Brett M. Colbert ◽  
Eric Nisenbaum ◽  
Aziz El-Amraoui ◽  
Derek M. Dykxhoorn ◽  
...  
Keyword(s):  
Stem Cells ◽  
Gene Therapy ◽  
Hearing Loss ◽  
Treatment Modalities ◽  
Versus Gene ◽  
Vitro Model ◽  
New Treatment ◽  
Induced Pluripotent ◽  
Therapy Strategies

AbstractProgressive non-syndromic sensorineural hearing loss (PNSHL) is the most common cause of sensory impairment, affecting more than a third of individuals over the age of 65. PNSHL includes noise-induced hearing loss (NIHL) and inherited forms of deafness, among which is delayed-onset autosomal dominant hearing loss (AD PNSHL). PNSHL is a prime candidate for genetic therapies due to the fact that PNSHL has been studied extensively, and there is a potentially wide window between identification of the disorder and the onset of hearing loss. Several gene therapy strategies exist that show potential for targeting PNSHL, including viral and non-viral approaches, and gene editing versus gene-modulating approaches. To fully explore the potential of these therapy strategies, a faithful in vitro model of the human inner ear is needed. Such models may come from induced pluripotent stem cells (iPSCs). The development of new treatment modalities by combining iPSC modeling with novel and innovative gene therapy approaches will pave the way for future applications leading to improved quality of life for many affected individuals and their families.

The Role of the Renin–Angiotensin System in the Cancer Stem Cell Niche

2021 ◽  
pp. 002215542110262
Author(s):  
Ethan J. Kilmister ◽  
Swee T. Tan
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Signaling Pathways ◽  
Renin Angiotensin System ◽  
Epidemiological Data ◽  
Malignant Cells ◽  
Angiotensin System ◽  
Renin Angiotensin

Cancer stem cells (CSCs) drive metastasis, treatment resistance, and tumor recurrence. CSCs reside within a niche, an anatomically distinct site within the tumor microenvironment (TME) that consists of malignant and non-malignant cells, including immune cells. The renin–angiotensin system (RAS), a critical regulator of stem cells and key developmental processes, plays a vital role in the TME. Non-malignant cells within the CSC niche and stem cell signaling pathways such as the Wnt, Hedgehog, and Notch pathways influence CSCs. Components of the RAS and cathepsins B and D that constitute bypass loops of the RAS are expressed on CSCs in many cancer types. There is extensive in vitro and in vivo evidence showing that RAS inhibition reduces tumor growth, cell proliferation, invasion, and metastasis. However, there is inconsistent epidemiological data on the effect of RAS inhibitors on cancer incidence and survival outcomes, attributed to different patient characteristics and methodologies used between studies. Further mechanistic studies are warranted to investigate the precise effects of the RAS on CSCs directly and/or the CSC niche. Targeting the RAS, its bypass loops, and convergent signaling pathways participating in the TME and other key stem cell pathways that regulate CSCs may be a novel approach to cancer treatment:

Telomere Length of Hematopoietic Cells in Long-Term Post-Autograft Survivors: No Evidence of Accelerated Replicative Cell Senescence Despite the Persistent Reduction of Both Committed and Immature Progenitor Cell Compartments.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4123-4123
Author(s):  
Alberto Rocci ◽  
Irene Ricca ◽  
Chiara Della Casa ◽  
Paolo Longoni ◽  
Mara Compagno ◽  
...  
Keyword(s):  
Stem Cells ◽  
Telomere Length ◽  
Progenitor Cell ◽  
Hematopoietic Cells ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Replicative Stress

Abstract Telomere length is considered a valuable replicative capacity predictor of human hematopoietic stem cells. Indeed, a progressive telomere shortening affects hematopoietic cells upon in vitro expansion. However, less is known on the dynamics of telomere shortening in vivo following a non-physiological replicative stress. Aim of this study was to investigate markers for cellular senescence of hematopoietic cells exposed to replicative stress induced by bone marrow reconstitution following stem cell autograft. Thus, both telomere length and in vitro functional characteristics of bone marrow (BM) and peripheral blood (PB) were evaluated at long-term in subjects who had received intensive chemotherapy and autograft. Thirty-two adults with a previous diagnosis of lymphoma were examined, at a median time of 73 months (range 42–125) since autograft. They all had received a high-dose sequential chemotherapy treatment followed by peripheral blood progenitor cell (PBPC) autograft. There were 20 male and 12 female (median age at autograft: 40 yrs., range 21–60). A Southern blot procedure using a chemiluminescence-based assay was employed to determine telomere length on samples from grafted PBPC as well as on BM and PB samples obtained at long-term during follow-up. These latter samples were also studied for their in vitro growth characteristics, assessed by short and long-term culture assays. In all cases, autograft had been performed with large quantities of hematopoietic stem cells (median autografted CD34+ve cells/kg: 9.8 x 106, range 2–24), allowing a rapid and stable hematologic reconstitution. Telomere length was found slightly shorter in BM mononuclear cells from samples taken at follow-up compared to samples from grafted material (median telomere length: 6,895 bp vs 7,073 bp, respectively; p=ns). No marked differences were observed in telomere evaluation between BM and PB cells. No significant differences were observed as well when PB telomere length of follow-up samples was compared with telomere length of PB from age-related normal subjects. BM and PB samples were then assessed for their in vitro growth characteristics. Committed and stromal progenitors were grown from all samples in good though variable quantities. However, as compared to normal controls, a statistically significant reduction of marrow-derived hematopoietic progenitors (CFU-GM - BFU-E - CFU-Mix) as well as stromal progenitors (CFU-F) was observed. Additionally, the more immature LTC-IC progenitor cell compartment was dramatically reduced, both in BM and PB samples. The results indicate that: i. the proliferative stress induced by intensive chemotherapy and post-graft hematopoietic reconstitution does not imply marked telomere loss in BM and PB cells at long-term, provided that large quantities of PBPC are used for autograft; ii. stem cells present in the graft or surviving after high-dose therapy are capable of reconstituting a sufficiently adequate hematopoiesis although the committed progenitor cell compartment and even more the immature LTC-IC progenitors are persistently reduced even at up to 10 years since autograft.

Development and regeneration in the central nervous system

1990 ◽  
Vol 327 (1239) ◽  
pp. 127-143 ◽  
Keyword(s):  
Stem Cells ◽  
Central Nervous System ◽  
Nervous System ◽  
Progenitor Cells ◽  
Progenitor Cell ◽  
Cell Types ◽  
The Central Nervous System

As part of our attempts to understand principles that underly organism development, we have been studying the development of the rat optic nerve. This simple tissue is composed of three glial cell types derived from two distinct cellular lineages. Type-1 astrocytes appear to be derived from a monopotential neuroepithelial precursor, whereas type-2 astrocytes and oligodendrocytes are derived from a common oligodendrocyte-type-2 astrocyte (O-2A) progenitor cell. Type-1 astrocytes modulate division and differentiation of O-2A progenitor cells through secretion of platelet-derived growth factor, and can themselves be stimulated to divide by peptide mitogens and through stimulation of neurotransmitter receptors. In vitro analysis indicates that many dividing O-2A progenitors derived from optic nerves of perinatal rats differentiate symmetrically and clonally to give rise to oligodendrocytes, or can be induced to differentiate into type-2 astrocytes. O-2A perinatal progenitors can also differentiate to form a further O-2A lineage cell, the O-2A adult progenitor, which has properties specialized for the physiological requirements of the adult nervous system. In particular, O-2A adult progenitors have many of the features of stem cells, in that they divide slowly and asymmetrically and appear to have the capacity for extended self-renewal. The apparent derivation of a slowly and asymmetrically dividing cell, with properties appropriate for homeostatic maintenance of existing populations in the mature animal, from a rapidly dividing cell with properties suitable for the rapid population and myelination of central nervous system (CNS) axon tracts during early development, offers novel and unexpected insights into the possible origin of self-renewing stem cells and also into the role that generation of stem cells may play in helping to terminate the explosive growth of embryogenesis. Moreover, the properties of O-2A adult progenitor cells are consistent with, and may explain, the failure of successful myelin repair in conditions such as multiple sclerosis, and thus seem to provide a cellular biological basis for understanding one of the key features of an important human disease.

scholarly journals In vitro megakaryocytopoietic and thrombopoietic activity of c-mpl ligand (TPO) on purified murine hematopoietic stem cells

Blood ◽  
1994 ◽  
Vol 84 (12) ◽  
pp. 4045-4052 ◽  
Author(s):  
FC Zeigler ◽  
F de Sauvage ◽  
HR Widmer ◽  
GA Keller ◽  
C Donahue ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Progenitor Cell ◽  
Fetal Liver ◽  
Cell Suspension Cultures ◽  
Hematopoietic Stem ◽  
Kit Ligand ◽  
Stem Cell Populations

Recently, the ligand for c-mpl has been identified and cloned. Initial studies of this molecule indicate that it is the platelet regulatory factor, thrombopoietin (TPO). Previous work has indicated that c-mpl is expressed in very immature hematopoietic precursors and thus raised the possibility that TPO may act directly on the hematopoietic stem cell. Therefore, in these studies, we investigate the effects of TPO on hematopoietic stem cell populations isolated from the murine fetal liver and bone marrow. Cocultivation of stem cells with fetal liver stroma give rise to multilineage expansion of the stem cells but with little or no megakaryocytopoiesis. Addition of TPO to these cocultures gives significant megakaryocyte production. This production is enhanced in combination with Kit ligand or interleukin-3. The addition of TPO to stem cell suspension cultures produces a dynamic thrombopoietic system in which stem cells undergo differentiation to produce megakaryocytes and proplatelets. These experiments show that the megakaryocytopoietic and thrombopoietic activities of TPO are initiated at the level of an early progenitor cell or upon the hematopoietic stem cell.

Hematopoietic stem cells with controllable tEpoR transgenes have a competitive advantage in bone marrow transplantation

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3710-3715 ◽  
Author(s):  
Suzanne Kirby ◽  
William Walton ◽  
Oliver Smithies
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Erythropoietin Receptor ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Myeloid Progenitor ◽  
Colony Forming Units

Abstract In a previous study, it was found that a truncated erythropoietin receptor transgene (tEpoR tg) enables multilineage hematopoietic progenitor amplification after treatment with erythropoietin (epo) in vitro and in vivo. This study used competitive bone marrow (BM) repopulation to show that tEpoR tg facilitates transplantation by hematopoietic stem cells (HSC). Individual multilineage colonies, committed myeloid progenitor colonies, and lymphoid colonies (pre-B colony-forming units) were grown from the marrow of animals 6 months after they received a 50/50 mixture of transgene and wild-type BM cells. In epo-treated recipients, the transgene-bearing cells significantly outcompeted the wild-type cells (84%-100% versus 16%-0%, respectively). In recipients treated with phosphate-buffered saline, the repopulation was minimally different from the donor mixture (49%-64% transgene versus 51%-36% wild-type). The epo-induced repopulation advantage is maintained in secondary transplants. In addition, neither accelerated HSC depletion nor uncontrollable proliferation occurred during epo-stimulated serial transplants of transgene-containing BM. Thus, the tEpoR tg functions in a benign fashion in HSC and allows for a significant and controllable repopulation advantage in vivo without excessive HSC depletion relative to wild-type BM.

Coagulation Factor Thrombin Regulates Hematopoietic Stem and Progenitor Cell Egress and Mobilization Via PAR-1 & CXCR4 Upregulation, SDF-1 Secretion and EPCR Shedding

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2341-2341 ◽  
Author(s):  
Shiri Gur-Cohen ◽  
Tomer Itkin ◽  
Aya Ludin ◽  
Orit Kollet ◽  
Karin Golan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Progenitor Cells ◽  
Stromal Cells ◽  
Progenitor Cell ◽  
Single Injection ◽  
Hematopoietic Stem ◽  
Epcr Shedding

Abstract Abstract 2341 Hematopoietic stem and progenitor cell (HSPC) egress from the bone marrow (BM) to the circulation is tightly regulated and is accelerated during stress conditions. The G-protein-coupled receptor protease-activated receptor-1 (PAR-1) and its activator thrombin play an important role in coagulation following injury and bleeding. We report that a single injection of thrombin induced rapid HSPC mobilization within one hour, increasing circulating leukocytes, predominantly CFU-C and primitive Lin−/Sca-1+/c-Kit+ (SKL) progenitor cells. This rapid mobilization was preceded by a dramatic decrease of SDF-1 (CXCL12) in BM stromal cells, including rare Nestin+ mesenchymal stem cells (MSC) which functionally express PAR-1 and release SDF-1. Thrombin injection also increased expression of PAR-1 and CXCR4 by BM HSPC. These results suggest involvement of the coagulation cascade of thrombin & PAR-1 in rapid SDF-1 secretion from niche supporting BM stromal cells as part of host defense and repair mechanisms. Administration of a PAR-1 specific antagonist (SCH79797) upregulated BM SDF-1 levels and significantly reduced the amounts of circulating CFU-C and primitive SKL progenitor cells. In vitro stimulation of BM mononuclear cells with thrombin for 1 hour led to increased CXCR4 expression by Lin−/c-Kit+ progenitors, accompanied by enhanced spontaneous and SDF-1 induced migration. Of note, specific PAR-1 inhibition in vitro significantly reduced SDF-1-directed migration of Lin-/c-Kit+ progenitors. Mechanistically, we found that thrombin - activated PAR-1 induced the downstream p38 MAPK and eNOS (nitric oxide synthase) signaling pathways. Long term repopulating hematopoietic stem cells (HSC) in murine BM highly express endothelial protein C receptor (EPCRhigh) (Balazs & Mulligan et al Blood 2006; Kent & Eaves et al Blood 2009). EPCR is expressed primarily on endothelial cells (EC) and has anti coagulation and anti inflammatory roles. Surface EPCR expression on EC is downregulated by many factors, including PAR-1 activation by thrombin, a process which is termed shedding and is not fully understood. Importantly, we found that over 90% of BM CD45+/EPCRhigh long-term HSC express PAR-1 and that circulating primitive HSPC in the blood and spleen lack EPCRhigh expression. In addition, in-vivo thrombin administration downregulated EPCR from BM HSC via eNOS signaling, thus allowing the release of stem cells from their BM microenvironment anchorage to the circulation. Correspondingly, in eNOS deficient mice, thrombin failed to induce PAR-1 upregulation, EPCR shedding, and HSPC mobilization. Recently, we reported that the antioxidant NAC inhibits G-CSF induced mobilization (Tesio & Lapidot et al Blood 2011). Co-administration of G-CSF with NAC prevented PAR-1 upregulation, concomitantly with reduced HSPC mobilization and increased levels of EPCRhigh HSC in the BM. Treatment of PAR-1 antagonist with G-CSF inhibited PAR-1 and CXCR4 upregulation on BM leukocytes and immature Lin−/c-Kit+ cells accompanied by increased levels of BM EPCRhigh HSC and reduced HSPC mobilization. Tissue factor (TF) is the main initiator of the coagulation system via the formation of an enzymatic “prothrombinase complex” that converts prothrombin to active thrombin. Unexpectedly, we found a unique structure of cell clusters expressing TF, located preferentially in the trabecular-rich area of the femoral metaphysis in murine bone tips, a region highly exposed to osteoclast/osteoblast bone remodeling. In vitro, immature osteoclasts exhibited increased TF expression in cell fusion areas, suggesting that in vivo osteoclast maturation activates the coagulation thrombin/PAR-1 axis of HSPC migration to the circulation. Finally, mimicking bacterial infection a single injection of Lipopolysaccharide (LPS), rapidly and systemically upregulated TF in the murine BM. LPS treatment prompted an increase in thrombin generation and subsequently HSPC mobilization, which was blocked by the PAR-1 antagonist. In conclusion, our study reveals a new role for the coagulation signaling axis, which acts on both hematopoietic and stromal BM cells to regulate steady state HSPC egress and enhanced mobilization from the BM. This thrombin/PAR-1 signaling cascade involves SDF-1/CXCR4 interactions, immature osteoclast TF activity, Nestin+/PAR-1+ MSC secretion of SDF-1 and EPCR shedding from hematopoietic stem cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals In Vitro Maintenance of Highly Purified, Transplantable Hematopoietic Stem Cells

Blood ◽  
1997 ◽  
Vol 89 (12) ◽  
pp. 4337-4347 ◽  
Author(s):  
Kateri A. Moore ◽  
Hideo Ema ◽  
Ihor R. Lemischka
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Lines ◽  
Progenitor Cell ◽  
Stromal Cell ◽  
Fetal Liver ◽  
Cell Activity ◽  
Hematopoietic Stem ◽  
Stem Cell Activity

Abstract The cellular and molecular mechanisms that regulate the most primitive hematopoietic stem cell are not well understood. We have undertaken a systematic dissection of the complex hematopoietic microenvironment to define some of these mechanisms. An extensive panel of immortalized stromal cell lines from murine fetal liver were established and characterized. Collectively, these cell lines display extensive heterogeneity in their in vitro hematopoietic supportive capacity. In the current studies, we describe a long-term in vitro culture system using a single stromal cell clone (AFT024) that qualitatively and quantitatively supports transplantable stem cell activity present in highly purified populations. We show multilineage reconstitution in mice that received the equivalent of as few as 100 purified bone marrow and fetal liver stem cells cultured for 4 to 7 weeks on AFT024. The cultured stem cells meet all functional criteria currently ascribed to the most primitive stem cell population. The levels of stem cell activity present after 5 weeks of coculture with AFT024 far exceed those present in short-term cytokine-supported cultures. In addition, maintenance of input levels of transplantable stem cell activity is accompanied by expansion of other classes of stem/progenitor cells. This suggests that the stem/progenitor cell population is actively proliferating in culture and that the AFT024 cell line provides a milieu that stimulates progenitor cell proliferation while maintaining in vivo repopulating activity.

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