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Hum. Reprod. Advance Access originally published online on November 2, 2007
Human Reproduction 2008 23(1):139-143; doi:10.1093/humrep/dem342
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© The Author 2007. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Endometrial endothelial cells are derived from donor stem cells in a bone marrow transplant recipient

M. Mints1, M. Jansson2, B. Sadeghi2, M. Westgren1, M. Uzunel3, M. Hassan2 and J. Palmblad2,5

1 Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology, Karolinska University Hospital Huddinge, S-141 86 Stockholm, Sweden 2 Experimental Cancer Medicine Centre, Department for Laboratory Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden 3 Division of Clinical Immunology, Karolinska University Hospital Huddinge, Stockholm, Sweden 4 Center for Inflammation and Hematology Research at the Department of Medicine Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden

5 Correspondence address. Tel: +46-8-58580000; Fax: +46-8-58587575; E-mail: miriam.mints{at}telia.com


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Funding
 Author contributions
 Acknowledgements
 References
 
BACKGROUND: The endometrium is a dynamic, cyclically regenerating tissue: a unique model of physiological angiogenesis in adults. However, the source of new endothelial cells (ECs) for vessel regrowth is obscure. We studied if male EC could be detected in the endometrial blood vessels of female human or mouse recipients of haematological stem cells from male donors.

METHODS: Endometrial biopsies, obtained from one patient after non-myeloablative allogeneic bone marrow transplantation and two controls, were analysed by immunohistochemistry of CD34 and VEGFR2 antibodies for the immunophenotyping of EC, and FISH probes for the detection of donor cells. Chimerism was analysed using real-time PCR. The same experiment was also applied on the animal model.

RESULTS: At the time of a Caesarean section in a female bone marrow transplanted patient, an average 14% of her endometrial EC were donor-derived. One year later, that figure was 10%. In contrast, none of two non-transplanted females demonstrated a mismatch in endometria at Caesarean section. In samples from female mice, harvested 40 days after a haematological stem cell transplant, a 6% average of donor-derived EC was detected.

CONCLUSIONS: Bone marrow-derived endothelial progenitors contribute to the formation of new blood vessels in the endometrium.

Key words: angiogenesis/endometrium/stem cells/bone marrow transplantation


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Funding
 Author contributions
 Acknowledgements
 References
 
The adult uterine endometrium is a most dynamic, richly vascularized human tissue. Within 5–6 days after onset of menstruation, the old endometrial lining is removed and a new one is regenerated, without scarring. This remarkable example of physiological angiogenesis and tissue remodelling in the adult occurs 300–400 times during a woman's lifetime.

Angiogenesis results either from sprouting of new vessels through recruitment of local endothelial cells (ECs) from neighbouring blood vessels, and/or by endothelial progenitor cells (EPCs) circulating in the peripheral blood after release from the bone marrow (Tepper et al., 2003Go; Grove et al., 2004Go; Jiang et al., 2004Go; Urbich and Dimmeler, 2004Go; Peters et al., 2005Go). Bone marrow stem cells also contribute to regeneration of the endometrium (Taylor, 2004Go). However, it is not known whether bone marrow-derived EPCs play a role for angiogenesis in the human endometrium.

Here, we wanted to see if bone marrow-derived EPCs of donor origin after bone marrow transplantation (BMT) contribute to neovascularization of the human endometrium and whether a mouse haematopoietic stem cell transplantation (HSCT) model reflects the human condition. We took advantage of the extremely rare occasion of a pregnancy and subsequent normal menstruations in a BMT recipient.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Funding
 Author contributions
 Acknowledgements
 References
 
Subjects
A 30-year-old female underwent a non-myeloablative allogeneic BMT at Umeå University Hospital (Sweden) in April 2002 for aplastic anaemia, with cells from a brother. The standard conditioning regimen consisted of cyclophosphamide plus 3 days of antithymocyte globulin. The BMT recipient menstruated normally for at least one year before becoming pregnant, which occurred two years after BMT. The pregnancy ended at 36 weeks with a Caesarean section because of intrauterine growth retardation; a male child was born. Endometrial biopsies were obtained during the section, and on follow-up one year later by means of a standard endometrial biopsy.

Endometrial biopsies were also obtained during Caesarean section from two healthy non-transplanted women giving birth to boys. Biopsies were formaldehyde fixed and paraffin embedded or snap-frozen at –70°C.

The study was approved of the Ethics Committee of the Karolinska Hospital. All women gave their informed consent to the study.

Animals and treatment
We also compared our results from bone marrow transplanted patient to an animal model. The mouse is a well-established model for investigating endometrial function: mouse endometrium undergoes cycles of cellular changes during its 4-days estrous cycle. Asahara et al. (1997)Go reported isolation of circulating endothelial progenitors cells, which possess the ability to incorporate into newly forming blood vessels. Furthermore, the same authors demonstrated the incorporation of bone marrow-derived EPCs in physiological neovascularization in uterine endometrial formation following induced ovulation as well as estrogen administration in transgenic mice (Takahashi et al., 1999Go). Hence, we adopted the following protocol.

Mice used here were included in various HSCT protocols in order to define optimal conditions for the procedure (Nilsson et al., 2005Go; Sjoo et al., 2006Go). Female and male BALB/c (H-2d) mice (7–8 weeks old and weighting 18–22 g each) were considered as recipients and donors, respectively. Recipient mice received cyclophosphamide (100 mg/kg/day) i.p. for two consecutive days followed by liposomal busulphan (15 mg/kg/day) administered i.p. as twice a day for four consecutive days.

Preparation of liposomal busulphan and cyclophosphamide was prepared as described previously (Hassan and Ehrsson, 1983Go; Hassan et al., 1998Go). Treatment started 7 days before BMT (Day –7). A control group of mice were inhabitants of the same environment as the treated mice, but received no treatment.

Two transplanted and two control mice were sacrificed on Day +40 after HSCT. Briefly, Sca-1+ cells were positively isolated from the bone marrow of male donor mice and infused into a tail vein of female mice (400 000 cells/mouse). Uteri were fixed in formaldehyde and paraffin embedded as described (Mints et al., 2005Go). Sections of 4 µm were then used for immunostaining and FISH.

Laboratory methods
Immunostaining protocols for endothelial cell characterization
CD34 and VEGFR2 antibodies were used for the immunophenotyping of EC, while XY FISH probes were used for detection of donor cells (Weber-Matthiesen et al., 1995Go). Antigen retrieval of paraffin-embedded samples was performed as described (Mints et al., 2005Go). The immunophenotyping was performed stepwise with species-specific antibodies, starting with CD34 staining and followed by VEGFR2. Double-positive cells had to be part of typical blood vessels, with a distinct lumen on longitudinal or cross-section, preferentially filled with erythrocytes, and located in the endometrial functionalis layer.

For staining of the human tissues, we used the following: a mouse anti-human CD34 monoclonal, QBEnd 10 (AM236-5M, BioGenex, San Ramon, CA, USA), and as the second antibody, Alexa fluor 488 goat anti-mouse F(ab’)2–fragment (Molecular Probes, Eugene, OR, USA). For VEGFR2 identification, a mouse anti-human VEGFR2 (Flk-l) monoclonal IgG1, (SDS sc-6251; Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA) was used and the secondary antibody for this was a Cy3-labelled rabbit anti-mouse (Jackson Immuno Research Laboratories, West Grove, PS, USA).

For the mouse studies, we used the following: an anti-mouse CD34 monoclonal antibody IgG2a, (Cedelane CL, Hornby, Ontario, Canada), a secondary biotinylated rabbit anti-rat antibody (Vector BA4001; Vector Laboratories Inc. Burlingame, CA, USA), visualized either with AMCA streptavidin (Jackson Immuno Research) or with Chromogen Fast-red (BioGenex). The second part of the double staining was performed in the following manner: a primary polyclonal rabbit anti-mouse antibody to VEGFR2 (also known as Flk-1), IgG, (SDS sc-504; Santa Cruz Biotechnology Inc.), and Alexa Fluor 488 goat anti-rabbit as the secondary antibody (A11 008, Molecular Probes).

Single staining of each antibody and blank controls were also done, both in the mouse and the human protocols. Staining without the primary or secondary antibody also served as controls.

Counterstaining was performed with DAPI (4',6-diamidino-2-phenylindole, Vector) in order to visualize cell nuclei.

A combination of fluorescence immunophenotyping and interphase cytogenetics was used to see if allogeneic-transplanted haematopoietic stem cells are able to proliferate locally to ECs.

Probes and protocols for FISH
FISH was performed after the immunophenotyping without further pre-treatment. For mouse specimens, we used a total paint chromosome Y DNA probe, Cy3 and FITC labeled (Cambio, Cambridge, UK), and for human cells, a centromeric probe, Vysis CEPXY (Abbott-Vysis Inc Downers Grove, IL, USA) was used. Protocols for FISH procedures from the manufacturers were followed. The preparations were mounted in VectaShield antifade solution (Vector Laboratories).

Detection and quantification of donor-derived endometrial ECs
Analyses were done in an Olympus fluorescence microscope BH60 with appropriate filter set equipped with a CCD camera and connected to a CytoVision image analysis system (Applied Imaging Corp, Ca, USA) in which the results were documented. We named each captured high-power field as an image.

All preparations were completely examined under the fluorescence microscope using an oil immersion objective with magnification 100 x 1.3. For each specimen, 10 adequate vision fields (~100 cells/field) were chosen in a uniform way, always starting at the left upper side of the specimen. In each field, the number of CD34 positive, VEGFR2 positive and double-positive cells carrying Y or no Y (mouse) were categorized and counted. For analyzing the human preparation, the chosen FISH probe made it possible to categorize for X, XX, XY or single Y cells. When the 4 µm sections were prepared some cells were cut so that sex chromosomes were not identifiable but cells were positive for CD34 and/or VEGFR2; thus, the sums of columns in Table I might not be identical.


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  		Table I. Detection of Y+ donor ECs in the endometrial vessels. ECs were characterized by simultaneous positivity for CD34 and VEGFR2. The figures represent the sums or mean percentages of positive cells per 10 high power microscopic fields. 1000 cells were counted

 
For each specimen in selected areas with blood vessels, 10 images were taken in a uniform way, always starting at the left upper side of the specimen. In each image the number of CD34 positive, VEGFR2 positive and XX positive/or XY positive cells were counted using 100x (high power field) ocular magnification.

Endometrial ECs were categorized as donor cells if they carried one Y chromosome signal in the mouse specimens and if they carried an XY or one Y centromeric signal in the human.

In the human controls, the percentage of X or XX positive cells was 80%. The corresponding figure for mouse samples was 83%.

Chimerism analyses using real-time PCR and SNP markers
Primers and probes for chimerism analysis were performed as described (Alizadeh et al., 2002Go). A set of 11 biallelic genetic systems with 19 markers were used to screen DNA samples. An allele was informative when positive for the individual of interest, but negative for the two others. We found an informative marker each for both the BMT donor and the son.

Detection and quantification of the DNA of interest from endometrial samples was performed on the ABI 7000 Sequence Detection System (Applied Biosystems, Foster City, CA, USA) using TaqMan technology. PCR parameters were standard and the reactions were performed in a total volume of 25 µl including 1x TaqMan Universal PCR Master Mix (Applied Biosystems), 5 µl of DNA sample, 300 nM of each primer and 200 nM probe. The amount of amplifiable DNA in each sample was assessed by parallel amplification of the reference gene GAPDH (glyceraldehyde phosphate dehydrogenase).

All samples were run in duplicate and the DNA samples from the pre-BMT patient, the donor and the son were included in each run. Relative quantification of DNA of interest was calculated according to the {Delta}{Delta}Ct method using GAPDH as a reference gene and the positive control sample as a calibrator. The formula used was 2–({Delta}CtU – {Delta}CtC), where {Delta}Ct = Ct target gene—Ct reference gene. U is the unknown sample and C is the calibrator sample.

Ethical approval
All experiments described herein were approved by the regional ethics committee for animal research in accordance with the Animal Protection Law, the Animal Protection Regulation and the regulations of the Swedish National Board for Laboratory Animals.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Funding
 Author contributions
 Acknowledgements
 References
 
Human samples
Two uterine biopsies from each sampling occasion were analysed for the BMT patient, and also two biopsies were used for each control. For each microscopic section, 10 visual fields were analysed. The analyses were based on 100 cells per field. We observed that in the patient, on average 14.2% (SE 7.1) of all ECs displayed the XY genotype at the time of the Caesarean section. One year later, 9.6% (SE 3.0) of all ECs were carrying the Y chromosome (Table I, Fig. 1). In the controls, no XY-positive cells were observed (Table I, Fig. 1).


Figure 1
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  		Figure 1: Immunohistochemical staining of endometrial blood vessels visualized by light and fluorescent microscopy (A–D) Mouse samples. (A) A section was immunostained for CD34 and detected with a Fast-red–conjugated secondary antibody. Then, it was examined by light microscopy with a 20x objective. Section was counter-stained with Harris' haematoxylin. The frame shows a vessel which then was examined further in (B–D). (B) Section was immunoassayed for CD34 (detected with AMCA, blue) and then stained for the Y chromosome (green spot with arrow) and examined in the fluorescent mode with a 100x objective. (C) Section was immunoassayed for VEGFR2 with Cy3-detected (red) antibodies and then examined by fluorescent microscopy with a 100x objective. The arrow indicates a signal spot for a mouse Y chromosome. (D) Section was double stained for CD34 and VEGFR2 (as in B and C) and then examined by fluorescent microscopy with a 100x objective. The arrows indicates a signal spot for a mouse Y chromosome. (E–H) Samples from human control. Endometrial biopsies were stained for CD34 (Alexa fluor 488, green), VEGF (Cy3, red) and, when co-localized, a yellow colour appeared. Cell nuclei were counterstained with DAPI (blue). The Y chromosome was stained green and the X chromosome was stained red. (E) Section from a control was immunoassayed by double staining for CD34 and VEGFR2 in the fluorescent mode with a 20x objective. The two stains were co-localized, resulting in yellow colour. The frame shows a vessel which then was examined further in (F–H). (F) Section was immunoassayed for CD34 in the fluorescent mode with a 100x objective. Arrows indicate signal spots for human X chromosomes. (G) Section was immunoassayed for VEGFR2 in the fluorescent mode with a 100x objective. Arrows indicate signal spots for human X chromosomes. (H) Sample was immunoassayed by double staining for CD34 and VEGFR2 in the fluorescent mode with a 100x objective. The two stains were co-localized, resulting in yellow colour. Arrows indicate signal spots for human X chromosomes. (I–L) Samples from BMT patient. Endometrial biopsies were stained for CD34 (Alexa fluor 488, green), VEGF (Cy3, red) and, when co-localized, a yellow colour appeared. Cell nuclei were counterstained with DAPI (blue). The Y chromosome was stained green and the X chromosome was stained red. (I) An endometrial biopsy BMT patient sample was immunoassayed by double staining for CD34 and VEGFR2 in the fluorescent mode with a 20x objective. The two stains were co-localized and resulting in yellow colour. The frame shows a vessel which then was examined further in (J–L). (J) Sample was immunoassayed for CD34 in the fluorescent mode with a 100x objective. Arrows indicate signal spots for Y chromosomes in CD34+ cells. (K) Sample was immunoassayed for VEGFR2 (Cy3) in the fluorescent mode with a 100x objective. Arrows indicate signal spots for Y chromosomes in VEGFR2+ cells. (L) Sample was immunoassayed by double staining for CD34 and VEGFR2 in the fluorescent mode with a 100x objective. The two stains were co-localized and resulting in yellow colour. Arrows indicate signal spots for Y chromosomes in the double-positive cells

 
In order to define if XY positive human endometrial ECs were of donor or offspring origin, we performed real-time PCR and identified SNP markers. ECs of male origin were detected in endometrial samples from the BMT patient by means of the PCR technique. In the sample obtained at Caesarean section, 30% of the DNA originated from the BMT donor, while ~5% was from the son. One year later, the amount of DNA from the BMT donor decreased to ~5%, while no DNA from the son was detected.

Mouse samples
Two slides were analysed from each uterus from control and recipient mice. Using the same definitions as for human specimens, we identified ECs as double-positive for CD34 and VEGFR2. In samples from recipient female mice, an average 6.2% (SE 2.2) XY-positive cells were detected (Table I, Fig. 1).


   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Funding
 Author contributions
 Acknowledgements
 References
 
The endometrium is a remarkable organ, where the vasculature is exchanged at every menstrual cycle. Hence, it is a most adequate organ to assess the role of endothelial progenitors for angiogenesis.

Our study has taken advantage of the very rare event, that is BMT patient becomes pregnant, delivers a healthy child and then regains menstrual cycles. This event offers a unique possibility to assess the origin of cells in the reproduction tract. We focused on the rapidly expanding ECs of endometrium during this pregnancy and one year later. To the best of our knowledge, this is the first study of its kind.

Previous studies in reproductive biology have focused on the interaction between bone marrow and ovaries (Johnson et al., 2005Go). Eggan et al. (2006)Go investigated the capacity of naturally circulating peripheral blood cells to contribute to oogenesis. They found no evidence that bone marrow cells, or any other normally circulating cells, contribute to the formation of mature, ovulated oocytes.

Furthermore, there are two previous studies on the presence of donor-derived endothelium. One concerned vessels in the skin and gastrointestinal tract of human allogeneic stem-cell transplantation recipients, and such ECs persisted for >7 years (Jiang et al., 2004Go). The second, performed in mice, found that bone marrow-derived EPCs may participate in neovascularization of the endometrium and glandular regrowth (Kearns and Lala, 1982Go). Taylor et al. (2004)Go demonstrated that human bone marrow stem cells contributed to endometrial regeneration after BMT, but results for ECs were not reported. Since the BMT cell population is heterogeneous, we confirmed our data on ECs with results from a HSCT model.

Our study is specific for ECs, showing that in humans and mice, donor-derived bone marrow stem cells differentiated into cells, displaying characteristics of ECs; thus, they were located in the vessel wall and expressed both CD34 and VEGFR2. Hence, they were not extramedullary haematopoietic stem cells, but were established as cells of the endothelial lineage (Choi et al., 1998Go; Peichev et al., 2000Go).

Furthermore, FISH analyses revealed two sex chromosomes in 54% of ECs, which is the expected frequency given the 4 µm thinness of section used (Spyridonidis et al., 2004Go). None of examined ECs had more than two sex chromosomes, consistent with an absence of cell fusion.

The presence of donor-derived ECs suggests that such cells persist in the endometrium for (at least) four years after BMT, suggesting a self-renewal potential of endothelial stem cell activity. Moreover, our results with human samples were confirmed by the animal experiment: donor endothelium in mouse uteri persisted for 40 days after engraftment.

In the patient, 9.6–14.2% of cells in endometrial blood vessels were donor-derived, suggesting that angiogenesis in the endometrium develops not only from local ECs, but also from EPCs derived from bone morrow. However, the majority of new ECs in the active and menstruating endometrium appear to be formed from local ECs of recipient's origin. It cannot be excluded that some positive ECs, in fact, were derived from the son at the time of the Caesarean section.

To conclude, bone marrow-derived EPCs contribute to neovascularization of the endometrium. Biopsies from endometrium which is a feasible and cost-effective method may represent a novel approach to study bone marrow-derived EPCs. Finally, the interaction between bone marrow and endometrium needs further study in patients with menstrual disorders.


   Funding
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Funding
Author contributions
 Acknowledgements
 References
 
This study was supported by grants from The Regional Agreement on Medical Training and Clinical Research (ALF) between Stockholm County Council and the Karolinska Institute, the Swedish Medical Research Council (19X-05 991, 71XS-13 135), the Karolinska Institutet, and Swedish Labour Market Insurance.


   Author contributions
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Funding
 Author contributions
Acknowledgements
 References
 
Study concept and design: M.M., M.H., M.W. and J.P.; Statistical analysis: M.M., M.J. and M.H.; Acquisition of data: M.M., M.J., B.S., M.U. and J.P.; Analyses and interpretation of data: M.M., M.J., M.H. and J.P.; Drafting of the manuscript: M.M., B.S., M.U., M.J. and J.P.; Critical revision of the manuscript for important intellectual content: M.M., M.J., M.H., M.W. and J.P.; Administrative, technical and material support: M.M, M.J., B.S., M.U. and M.H.


   Acknowledgements
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Funding
 Author contributions
 Acknowledgements
References
 
The skilful technical assistance by Mrs Annette Landström, Mrs Inger Vedin and Bo Blomgren, MD PhD is acknowledged.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Funding
 Author contributions
 Acknowledgements
 References
 
Alizadeh M, Bernard M, Danic B, Dauriac C, Birebent B, Lapart C, Lamy T, Le Prise PY, Beauplet A, Bories D, et al. Quantitative assessment of hematopoietic chimerism after bone marrow transplantation by real-time quantitative polymerase chain reaction. Blood (2002) 99:4618–4625.[Abstract/Free Full Text]

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Choi K, Kennedy M, Kazarov A, Papadimitriou JC, Keller G. A common precursor for hematopoietic and endothelial cells. Development (1998) 125:725–732.[Abstract]

Eggan K, Jurga S, Gosden R, Min IM, Wagers AJ. Ovulated oocytes in adult mice derive from non-circulating germ cells. Nature (2006) 441:1109–1114.[CrossRef][Medline]

Grove JE, Bruscia E, Krause DS. Plasticity of bone marrow-derived stem cells. Stem Cells (2004) 22:487–500.[CrossRef][Web of Science][Medline]

Hassan M, Ehrsson H. Gas chromatographic determination of busulfan in plasma with electron-capture detection. J Chromatogr (1983) 277:374–380.[Web of Science][Medline]

Hassan M, Hassan Z, Nilsson C, Rehim MA, Kumlien S, Elfsson B, Kallberg N. Pharmacokinetics and distribution of liposomal busulfan in the rat: a new formulation for intravenous administration. Cancer Chemother Pharmacol (1998) 42:471–478.[CrossRef][Web of Science][Medline]

Jiang S, Walker L, Afentoulis M, Anderson DA, Jauron-Mills L, Corless CL, Fleming WH. Transplanted human bone marrow contributes to vascular endothelium. Proc Natl Acad Sci USA (2004) 101:16891–16896.[Abstract/Free Full Text]

Johnson J, Bagley J, Skaznik-Wikiel M, Lee HJ, Adams GB, Niikura Y, Tschudy KS, Tilly JC, Cortes ML, Forkert R, et al. Oocyte generation in adult mammalian ovaries by putative germ cells in bone marrow and peripheral blood. Cell (2005) 122:303–315.[CrossRef][Web of Science][Medline]

Kearns M, Lala PK. Bone marrow origin of decidual cell precursors in the pseudopregnant mouse uterus. J Exp Med (1982) 155:1537–1554.[Abstract/Free Full Text]

Mints M, Blomgren B, Falconer C, Fianu-Jonasson A, Palmblad J. Microvascular density, vascular endothelial growth factor A, and its receptors in endometrial blood vessels in patients with menorrhagia. Fertil Steril (2005) 84:692–700.[CrossRef][Web of Science][Medline]

Nilsson C, Forsman J, Hassan Z, Abedi-Valugerdi M, O'Connor C, Concha H, Jansson M, Hassan M. Effect of altering administration order of busulphan and cyclophosphamide on the myeloablative and immunosuppressive properties of the conditioning regimen in mice. Exp Hematol (2005) 33:380–387.[CrossRef][Web of Science][Medline]

Peichev M, Naiyer AJ, Pereira D, Zhu Z, Lane WJ, Williams M, Oz MC, Hicklin DJ, Witte L, Moore MA, et al. Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood (2000) 95:952–958.[Abstract/Free Full Text]

Peters BA, Diaz LA, Polyak K, Meszler L, Romans K, Guinan EC, Antin JH, Myerson D, Hamilton SR, Vogelstein B, et al. Contribution of bone marrow-derived endothelial cells to human tumor vasculature. Nat Med (2005) 11:261–262.[CrossRef][Web of Science][Medline]

Sjoo F, Hassan Z, Abedi-Valugerdi M, Griskevicius L, Nilsson C, Remberger M, Aschan J, Concha H, Gaughan U, Hassan M. Myeloablative and immunosuppressive properties of treosulfan in mice. Exp Hematol (2006) 34:115–121.[CrossRef][Web of Science][Medline]

Spyridonidis A, Schmitt-Graff A, Tomann T, Dwenger A, Follo M, Behringer D, Finke J. Epithelial tissue chimerism after human hematopoietic cell transplantation is a real phenomenon. Am J Pathol (2004) 164:1147–1155.[Abstract/Free Full Text]

Takahashi T, Kalka C, Masuda H, Chen D, Silver M, Kearney M, Magner M, Isner JM, Asahara T. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med (1999) 5:434–438.[CrossRef][Web of Science][Medline]

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Tepper OM, Sealove BA, Murayama T, Asahara T. Newly emerging concepts in blood vessel growth: recent discovery of endothelial progenitor cells and their function in tissue regeneration. J Investig Med (2003) 51:353–359.[Web of Science][Medline]

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Submitted on July 10, 2007; resubmitted on September 11, 2007; accepted on September 26, 2007.


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