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First published online June 7, 2005
Stem Cells Vol. 23 No. 7 August 2005, pp. 874 -878
doi:10.1634/stemcells.2005-0012; www.StemCells.com
© 2005 AlphaMed Press

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Comparison of Various Bone Marrow Fractions in the Ability to Participate in Vascular Remodeling After Mechanical Injury

Makoto Saharaa, Masataka Sataa,b,d, Yumi Matsuzakic,e, Kimie Tanakaa, Toshihiro Moritaa, Yasunobu Hirataa, Hideyuki Okanoc,e, Ryozo Nagaia

a Departments of Cardiovascular Medicine and
b Advanced Clinical Science and Therapeutics, University of Tokyo Graduate School of Medicine, Tokyo, Japan;
c Department of Physiology, Keio University School of Medicine, Tokyo, Japan;
d PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan;
e CREST, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan

Key Words. Endothelial cells • Hematopoietic stem cells • Progenitor • Smooth muscle cells • Transdifferentiation

Correspondence: Masataka Sata, M.D., Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Telephone: 81-3-3815-5411; Fax: 81-3-3814-0021; e-mail: msata-circ{at}umin.ac.jp


   ABSTRACT
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
In contrast to conventional assumption, recent reports propose the possibility that hematopoietic stem cells (HSCs) may have broader potential to differentiate into various cell types. Here, we tested the pluripotency of HSCs by comparing vascular lesions induced by mechanical injury after bone marrow reconstitution with total bone marrow (TBM) cells, c-Kit+ Sca-1+ Lin– (KSL) cells, or a single HSC cell (Tip-SP CD34–KSL cell, CD34– c-Kit+ Sca-1+ Lin– cell with the strongest dye-efflux activity) harboring green fluorescent protein (GFP). The lesions contained a significant number of GFP-positive cells in the TBM and KSL groups, whereas GFP-positive cells were rarely detected in the HSC group. These results suggest that transdifferentiation of a highly purified HSC seems to be a rare event, if it occurs at all, whereas bone marrow cells including the KSL fraction can give rise to vascular cells that substantially contribute to repair or lesion formation after mechanical injury.


   INTRODUCTION
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Recent evidence suggests that bone marrow–derived cells may participate in regeneration of remote organs [1]. Bone marrow contains both hematopoietic and nonhematopoietic cells. Hematopoietic stem cells (HSCs) are defined as having the capacity for self-renewal and the ability to differentiate into all mature hematopoietic lineages [2]. Although it was assumed that HSCs give rise to hematopoietic cells, recent reports proposed the possibility that HSCs may have the broader potential to differentiate into nonhematopoietic cells, including epithelial cells [3], hepatocytes [4, 5], cardiomyocytes [6], and vascular cells [7]. In contrast, others cast doubt on the pluripotency of adult HSCs under physiological conditions by analyzing uninjured organs of bone marrow chimeric mice [8].

There might be two possibilities that account for the discrepancy. First, the HSCs used differ in their purity [4, 7, 8]. Most of the studies analyzed the CD34–, c-Kit+, Sca-1+, Lineage– (CD34–KSL) bone marrow cells [4, 7], which have been assumed as the most primitive HSCs [9]. However, even in the best case series reported [9], only one in five recipients showed successful engraftment after single-cell transplantation, indicating that the CD34–KSL fraction represents a heterogeneous population containing nonhematopoietic cells. It is possible that nonhematopoietic cells among the CD34–KSL cells might be responsible for the pluripotency. Second, the apparent discrepancy could merely derive from the analysis of noninjured versus injured tissues [10]. We reported that the mode of injury is crucial for the recruitment of bone marrow–derived cells to vascular remodeling [11]. Thus, it remains unclear whether a highly purified single HSC can contribute to vascular remodeling after severe vascular injuries, which are essential for bone marrow–derived cells to participate in vascular remodeling.

Here, we transplanted either total bone marrow (TBM) cells, KSL fraction cells, or a highly purified HSC into lethally irradiated wild-type mice [2]. In all groups, peripheral blood cells were successfully reconstituted. However, bone marrow–derived cells were seldom detected in the injured artery when a single HSC was injected into irradiated mice. These results suggest that it is a rare property for a purified HSC to transdifferentiate into vascular cells.


   MATERIALS AND METHODS
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Animals
All wild-type mice were purchased from SLC (Shizuoka, Japan). Transgenic mice (C57BL/6 background) that ubiquitously express enhanced green fluorescent protein (GFP) were described in previous reports [2, 7]. All procedures involving experimental animals were performed in accordance with protocols approved by the institutional committee for animal research of the University of Tokyo and complied with National Institutes of Health guidelines.

Preparation of TBM Cells, KSL Cells, and a Highly Purified HSC
TBM cells were harvested from femora and tibias of the GFP-transgenic mice as previously described [7]. c-Kit+, Sca-1+, Lineage– fraction of bone marrow cells (KSL cells) were purified as described [7]. Briefly, TBM cells were stained with a cocktail of biotinylated monoclonal antibodies against lineage markers (B220/CD45R, clone RA3-6B2; Mac-1, clone M1/70; Gr-1, clone RB6-8C5; Thy1.2, clone 53-2.1; CD3, clone 145-2C11; CD4, clone GK1.5; CD8, clone 53-6.72; and TER 119, clone Ly-76; Pharmingen, San Diego, http://www.bdbiosciences.com/pharmingen) for 20 minutes at 4°C. The cells were treated with streptavidin-conjugated immunomagnetic beads (BioMag; Polysciences, Inc., Warrington, PA, http://www.polysciences.com/shop) for 30 minutes to remove highly lineage-positive cells. The remaining cells were collected and stained with a phycoerythrin (PE)–conjugated anti–Sca-1 antibody (Pharmingen), an allo-phycocyanin-conjugated anti–c-Kit antibody (Pharmingen), and PE Texas red–conjugated streptavidin (Pharmingen) for 20 minutes at 4°C. KSL cells were purified by fluorescence-activated cell sorting (ALTRA; Beckman-Coulter, Tokyo, http://www.beckmancoulter.com). The bone marrow cells that had the strongest dye-efflux activity (Tip–side population [SP] cells) with a phenotype of CD34– c-Kit+ Sca-1+ Lineage– (CD34–KSL) were isolated as described [2]. A single-cell transplantation analysis has revealed that the Tip-SP CD34–KSL cells represent the most primitive hematopoietic stem cells, with nearly complete hematopoietic engraftment activity [2].

Stem Cell Transplantation
After lethal irradiation of 10.5 Gy (MBR-1520RB; Hitachi, Tokyo, http://www.hitachi.com), 1 x 106 TBM cells (TBM group), 3 x 103 KSL cells (KSL group), or a single Tip-SP CD34–KSL cell (HSC group) from GFP-transgenic mice were suspended in 0.3 ml phosphate-buffered saline and injected intravenously by tail vein puncture into C57BL/6 mice. The sites of intravenous injection, that is, tail vein or retro-orbital plexus, had no effect on the level of reconstitution (Y. Matsuzaki and H. Nakauchi, unpublished observations). The single Tip-SP CD34–KSL cell was transplanted with 2 x 105 TBM cells from C57BL/6 mice for radioprotection. Eight to 16 weeks after transplantation, peripheral blood samples were collected from the retro-orbital venous plexus. After erythrocytes were lysed with ACK lysing buffer (0.155 M ammonium chloride, 0.1 M disodium EDTA, and 0.01 M potassium bicarbonate) [12], cell suspensions were analyzed by flow cytometry to measure GFP signal (XL; Beckman-Coulter).

Wire-Mediated Endovascular Injury and Histological Analysis
At 12 weeks after irradiation and stem cell transplantation, an endovascular arterial injury was induced to the femoral artery of the bone marrow chimeric mice by inserting a large wire (0.38 mm indiameter, No. C-SF-15-15 [Cook, Bloomington, IN, http://www.cookgroup.com/profile/med-mfg/index.html]) as described [7, 11, 13]. At 4 weeks, the injured femoral arteries were excised and fixed in 4% paraformaldehyde. To preserve GFP signal for histological analyses, the arteries were embedded in plastic resin (Technovit 8100; Heraeus Kulzer, Wehrheim, Germany, http://www.heraeus-kulzer-us.com) as described. Immunofluorescence double staining was performed as described elsewhere [7]. The plastic-embedded sections were incubated with primary antibodies (Cy3-conjugated anti–{alpha}-smooth muscle actin [{alpha}-SMA], clone 1A4 [Sigma, St. Louis, http://www.sigmaaldrich.com]; anti-CD31, clone MEC13.3 [BD Biosciences, San Jose, CA, http://www.bdbiosciences.com/index.shtml]; anti–pan-endothelial cell antigen, clone MECA-32 [BD Biosciences]; anti-CD45, clone 30-F11 [BD Biosciences]) followed by incubation with Cy3-conjugated secondary antibodies (Jackson ImmunoResearch, West Grove, PA, http://www.jacksonimmuno.com). Nuclei were counter-stained with Hoechst 33258 (Sigma). The sections were mounted with the ProLong Antifade Kit (Molecular Probes, Eugene, OR, http://probes.invitrogen.com) and observed under confocal microscopes (FLUOVIEW FV300; Olympus, Tokyo, http://www.olympus-global.com/en/global). Cell number was counted in the neointima and media of a cross-section of each artery [7, 11]. Frequency of GFP-positive cells among total cells is reported.

Statistics
The results are presented as the mean ± SE of the mean. Comparisons among the three groups were evaluated by one-way analysis of variance followed by Scheffe’s post hoc test. Statistical significance was defined as p < .05.


   RESULTS
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
Significant Engraftment of a Single Tip-SP CD34–KSL Cell
Either TBM cells (1 x 106, TBM group), c-Kit+, Sca-1+, Lin– cells (3 x 103, KSL fraction), or a single Tip-SP CD34–KSL cell (1, HSC fraction) were injected into lethally irradiated wild-type mice. Consistent with our previous report [2], a single Tip-SP CD34–KSL cell showed significant donor cell engraftment for long term (Figs. 1A, 1BGo). Consistent with our previous study [2], both myelocytes/monocytes and T/B lymphocytes derived from a single Tip-SP cell were detected at 3, 6, and 12 months after transplantation. Flow cytometry at 16 weeks after bone marrow reconstitution revealed that peripheral blood cells had been reconstituted with the injected cells in TBM (79.6% ± 5.1%), KSL (68.4% ± 5.1%), and HSC (34.4% ± 6.5%) groups (Fig. 1BGo).



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  		Figure 1. Successful engraftment of a single Tip-SP CD34–KSL cell, 1 x 106 total bone marrow (TBM group) cells (n = 4), 3 x 103 c-Kit+ Sca-1+ Lin– (KSL group) fraction cells (n = 6), or a single Tip-SP CD34–KSL cell (HSC group) (n = 7) harboring green fluorescent protein (GFP) were injected into lethally irradiated wild-type mice. (A): Proportion of the GFP-positive cells in peripheral blood after transplantation of a single Tip-SP CD34–KSL cell. Time courses of three representative mice are reported. (B): Representative flow cytometric histograms of peripheral leukocytes in TBM, KSL, and HSC groups at 16 weeks after transplantation. Abbreviations: HSC, hematopoietic stem cell; SP, side population.

 
Failure of a Single HSC-Derived Cell to Participate in Vascular Remodeling
Wire-mediated endovascular injury was induced to the femoral artery at 12 weeks after irradiation and injection. At 16 weeks after stem cell transplantation, the femoral arteries showed neointimal formation that mainly consisted of {alpha}-SMA–positive cells in all groups (Fig. 2AGo). The neointima contained a significant number of GFP-positive cells in the TBM group (24.0% ± 7.2%; n = 4) and the KSL group (14.1% ± 6.1%; n = 6). On the other hand, GFP-positive cells were seldom detected in the neointima of the HSC group (0.2% ± 0.1%; n = 7). Similarly, the media contained a significant number of GFP-positive cells in the TBM group (31.1% ± 11.2%) and KSL group (16.8% ± 6.6%). In contrast, GFP-positive cells were rarely detected in the media in the HSC group (2.7% ± 1.0%) (Fig. 2BGo, Table 1Go).



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  		Figure 2. Failure of a highly purified HSC to contribute to vascular remodeling after mechanical vascular injury. (A): Representative cross-sections of the vascular lesions. At 12 weeks after irradiation and stem cell transplantation, wire-mediated injury was induced in the femoral artery of the bone marrow chimeric mice. The injured arteries were harvested at 16 weeks, embedded in plastic resin, and observed under a confocal microscope (FLUOVIEW FV300; Olympus). Arrowheads indicate the internal elastic lamina. Arrow indicates a GFP-positive cell observed in adventitia in the HSC group. Bar = 50 µm. (B, C): Frequency of GFP-positive cells among the total cells in the(B) neointima and (C) media. *p <.05; **p < .01. Abbreviations: DIC, differential interference contrast; GFP, green fluorescent protein; HSC, hematopoietic stem cell; KSL, c-Kit+, Sca-1+, Lineage–; L, lumen; M, media; NI, neointima; TBM, total bone marrow.

 

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  		Table 1. Frequency of green fluorescent protein (GFP)–positive cells in neointima and media per a cross-section 4 weeks after vascular injury in bone marrow chimeric mice
 
Next, we characterized the bone marrow–derived cells observed in the vascular lesions. In the KSL group as well as in the TBM group, many GFP-positive cells expressed {alpha}-SMA in the neointima and media (Figs. 3A–3CGo). The bone marrow–derived cells on the luminal side were positive for endothelial markers (BS-lectin and CD31) (Figs. 3D, 3EGo), as previously reported [7]. In the HSC group, very few GFP-positive cells were detected in the lesions in the HSC group (Fig. 3CGo). All of the GFP-positive cells were positive for CD45 (Fig. 3FGo). We could not find GFP-positive cells that expressed {alpha}-SMA or endothelial markers.



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  		Figure 3. Double immunofluorescent images of the injured arteries. Plastic-embedded sections were stained for (A, B, C) {alpha}-smooth muscle actin ({alpha}-SMA, red), (D, E) CD31 (red), and (F) CD45 (red) followed by counterstaining with Hoechst 33258 (blue). Arrowheads indicate the internal elastic lamina. Arrows indicate green fluorescent protein–positive cells that were positive for markers. Bar = 10 µm. Abbreviations: HSC, hematopoietic stem cell; KSL, c-Kit+, Sca-1+, Lineage–; L, lumen; M, media; NI, neointima; TBM, total bone marrow.

 

   DISCUSSION
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
The present study was designed to rigorously determine the plasticity of an HSC in vivo by analyzing the vascular lesions induced by wire injury after bone marrow reconstitution with a single HSC. Although a single HSC showed an appreciable level of hematopoietic engraftment activity, very few cells in the lesion were derived from the single HSC. In contrast, the GFP-positive cells substantially contributed to vascular remodeling when bone marrow was reconstituted with TBM cells or KSL cells [7, 11].

The HSCs used in this study had the strongest dye-efflux activity with nearly complete level of hematopoietic engraftment activity [2]. We could detect the single Tip-SP CD34-KSL–derived cells not only in T/B lymphocytes but also in myeloid lineage even at 12 months after transplantation [2]. Given the short life of mature myeloid cells, the long-term chimerism in total hematopoietic cells supports the notion that the single Tip-SP CD34-KSL cell undergoes self-renewal and continuously gives rise to progenitors of T/B lymphocytes and myelocytes/monocytes. Moreover, the Tip-SP CD34-KSL cells are homogenous in size and morphology as determined by flow cytometric analysis of 10,000 Tip-SP CD34-KSL cells [2]. About 90% of the Tip-SP CD34-KSL cells can form huge colonies in colony assay (Y. Matsuzaki, unpublished observations). We assume that the diverse chimerism results from the difference in place where the transplanted Tip-SP CD34-KSL cell homes.

Our result suggests that it is rare for a highly purified HSC to transdifferentiate into vascular cells. In contrast, the KSL fraction of bone marrow cells contained a distinct population that could substantially contribute to lesion formation. Although the KSL fraction is considered to be enriched in HSCs [4], mesenchymal stem cells or multipotent cells that are more primitive than HSCs [14] could be included in this fraction. It is plausible that those nonhematopoietic cells in the KSL fraction might be responsible for the KSL-derived endothelial-like cells or smooth muscle–like cells observed in the vascular lesion.

Recent reports suggest that HSCs adopt tissue-specific phenotype by cell fusion but not by transdifferentiation [15]. Previous reports documented polyploidization of vascular smooth muscle cells in response to mechanical and humoral stimuli [16]. Thus, it is possible that cell fusion can account for, at least in part, the accumulation of bone marrow–derived smooth muscle–like cells in vascular lesions. However, we seldom detected the HSC-derived cells in the vascular lesions. It would be rare for an HSC to contribute to vascular remodeling even by cell fusion.


   CONCLUSION
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
Our finding suggests that a highly purified murine HSC seldom transdifferentiates into vascular cells. Distinct cell populations other than hematopoietic cells may be responsible for most bone marrow–derived smooth muscle–like cells and endothelial like–cells that could be observed in vascular lesions after mechanical injury.


   ACKNOWLEDGMENTS
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
This study was supported in part by grants from the Japanese Ministry of Education, Culture, Sports, Science, and Technology and from the Japanese Ministry of Health, Labor, and Welfare.


   REFERENCES
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

  1. Poulsom R, Alison MR, Forbes SJ et al. Adult stem cell plasticity. J Pathol 2002;197:441–456.[CrossRef][Medline]

  2. Matsuzaki Y, Kinjo K, Mulligan RC et al. Unexpectedly efficient homing capacity of purified murine hematopoietic stem cells. Immunity 2004;20:87–93.[CrossRef][Medline]

  3. Krause DS, Theise ND, Collector MI et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 2001;105:369–377.[CrossRef][Medline]

  4. Lagasse E, Connors H, Al-Dhalimy M et al. Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Nat Med 2000;6:1229–1234.[CrossRef][Medline]

  5. Jang YY, Collector MI, Baylin SB et al. Hematopoietic stem cells convert into liver cells within days without fusion. Nat Cell Biol 2004;6:532–539.[CrossRef][Medline]

  6. Orlic D, Kajstura J, Chimenti S et al. Bone marrow cells regenerate infarcted myocardium. Nature 2001;410:701–705.[CrossRef][Medline]

  7. Sata M, Saiura A, Kunisato A et al. Hematopoietic stem cells differentiate into vascular cells that participate in the pathogenesis of atherosclerosis. Nat Med 2002;8:403–409.[CrossRef][Medline]

  8. Wagers AJ, Sherwood RI, Christensen JL et al. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 2002;297:2256–2259.[Abstract/Free Full Text]

  9. Osawa M, Hanada K, Hamada H et al. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science 1996;273:242–245.[Abstract]

  10. Blau H, Brazelton T, Keshet G et al. Something in the eye of the beholder. Science 2002;298:361–362.

  11. Tanaka K, Sata M, Hirata Y et al. Diverse contribution of bone marrow cells to neointimal hyperplasia after mechanical vascular injuries. Circ Res 2003;93:783–790.[Abstract/Free Full Text]

  12. Okada S, Yoshida T, Hong Z et al. Impairment of B lymphopoiesis in precocious aging (klotho) mice. Int Immunol 2000;12:861–871.[Abstract/Free Full Text]

  13. Sata M, Maejima Y, Adachi F et al. A mouse model of vascular injury that induces rapid onset of medial cell apoptosis followed by reproducible neointimal hyperplasia. J Mol Cell Cardiol 2000;32:2097–2104.[CrossRef][Medline]

  14. Jiang Y, Jahagirdar BN, Reinhardt RL et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002;418:41–49.[CrossRef][Medline]

  15. Vassilopoulos G, Wang PR, Russell DW. Transplanted bone marrow regenerates liver by cell fusion. Nature 2003;422:901–904.[CrossRef][Medline]

  16. Campbell JH, Tachas G, Black MJ et al. Molecular biology of vascular hypertrophy. Basic Res Cardiol 1991;86:3–11.

Received January 11, 2005; accepted for publication May 19, 2005.



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