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Ann Thorac Surg 2002;74:19-24
© 2002 The Society of Thoracic Surgeons

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Original article: cardiovascular

Xenotransplant cardiac chimera: immune tolerance of adult stem cells

^a Division of Cardiac Surgery, McGill University Health Center, Montreal, Quebec, Canada
^b Division of Cardiovascular Surgery, Nagoya City University Medical School, Nagoya, Japan

Accepted for publication March 5, 2002.

* Address reprint requests to Dr Chiu, Division of Cardiac Surgery, The Montreal General Hospital, MUHC, 1650 Cedar Ave, Suite C9-169, Montreal, Quebec H3G 1A4, Canada
e-mail: rchiu{at}po-box.mcgill.ca

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. Bone marrow stromal cells have been shown to engraft into xenogeneic fetal recipients. In view of the potential clinical utility as an alternative source for cellular and gene therapies, we studied the fate of xenogeneic marrow stromal cells after their systemic transplantation into fully immunocompetent adult recipients without immunosuppression.

Methods. Bone marrow stromal cells were isolated from C57B1/6 mice and retrovirally transduced with LacZ reporter gene for cell labeling. We then injected 6 x 10⁶ labeled cells into immunocompetent adult Lewis rats. One week later, the recipient animals underwent coronary artery ligation and were sacrificed at various time points ranging from 1 day to 12 weeks after ligation. Hearts, blood, and bone marrow samples were collected for histologic and immunohistochemical studies.

Results. Labeled mice cells engrafted into the bone marrow cavities of the recipient rats for at least 13 weeks after transplantation without any immunosuppression. On the other hand, circulating mice cells were positive only for the animals with 1-day-old myocardial infarction. At various time points, numerous mice cells could be found in the infarcted myocardium that were not seen before coronary ligation. Some of these cells subsequently showed positive staining for cardiomyocyte specific proteins, while other labeled cells participated in angiogenesis in the infarcted area.

Conclusions. The marrow stromal cells are adult stem cells with unique immunologic tolerance allowing their engraftment into a xenogeneic environment, while preserving their ability to be recruited to an injured myocardium by way of the bloodstream and to undergo differentiation to form a stable cardiac chimera.

	Introduction

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Bone marrow stromal cells (MSCs) are adult stem cells capable of differentiating into cells of both mesenchymal and nonmesenchymal lineages [1–6]. When transfused intravenously, MSCs have been reported to engraft into the bone marrow compartment of allogeneic recipients without significant toxicity [7]. Liechty and colleagues [8] recently reported that human MSCs could engraft into the fetus of sheep after transplantation intraperitoneally, and persisted in the host organs for as long as 13 months without immunosuppression. Thus although precise mechanisms are still unknown, MSCs seem to have unique immunologic characteristics that allow their persistence in a xenogeneic fetal environment. However, whether or not these xenogeneic MSCs can engraft into fully immunocompetent adult animals after systemic administration and whether or not these cells, if they survive, still possess their abilities to migrate and to differentiate have not been demonstrated. In this study, we intravenously injected mice MSCs into rats and found their engraftment in the bone marrow of the recipients. Furthermore, we confirmed that these cells were capable of being recruited to an injured myocardium and undergo differentiation into several phenotypes, thus participating in the repair process.

	Material and methods

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Animals
Female C57Bl/6 mice and male Lewis rats were used in this study as the donors and recipients, respectively. All animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources, National Research Council, and published by the National Academy Press, revised 1996, and the "Guide to the Care and Use of Experimental Animals" of the Canadian Council on Animal Care.

Experimental design
Figure 1 shows an experimental design of this study. Isolated mice MSCs (3 x 10⁶) were injected into the penile vein of the recipients for 2 consecutive days. One week after the second injection, either left coronary artery ligation (MSC group) or sham operation (control group) was performed on the recipients. The animals were then sacrificed at various intervals after the procedure ranging from 1 day to 12 weeks.

View larger version (13K): [in this window] [in a new window]   Fig 1. Experimental design. (LCA = left coronary artery; MSCs = marrow stromal cells.)

Marrow stromal cells staining with 5-bromo-4-chloro-3-indoyl-ß-D-galactoside for detection of ß-galactosidase activity
Cells were plated in 35-mm dishes and were fixed in 1% glutaraldehyde for 5 minutes at room temperature, then they were washed with phosphate-buffered saline. Staining solution at pH of 7.8 to 8.0 [10], which contains 1 mg/mL 5-bromo-4-chloro-3-indoyl-ß-D-galactoside (X-gal), 1 mmol/L ethyleneglycol-bis(ß-aminoethyl-ether)-N,N'-tetraacetic acid, 5 mmol/L K₃Fe(CN)₆, 5 mmol/L K₄Fe(CN)₆O · 3 H₂O, 2 mmol/L magnesium chloride, and 0.01% sodium deoxycholate [9], was added. Then cells were incubated at 37°C and protected from light for 16 hours.

Transplantation of marrow stromal cells and ligation of the left coronary artery
Male Lewis rats (225 to 275 g) were used in this study as recipient animals. The animals were anesthetized with isoflurane (MTC Pharmaceuticals, Cambridge, Ontario, Canada), intubated, and mechanically ventilated at 80 breaths/min. Mice MSCs (3 x 10⁶ suspended in 150 µL of Dulbecco’s Modified Eagle’s Medium) were injected into the penile vein and were reinjected 24 hours later in the same manner. Total number of MSCs injected was 6 x 10⁶ per animal. One week after the second injection, the animals were again anesthetized as mentioned and underwent either coronary artery ligation or sham operation (left thoracotomy only) as previously described [9]. Animals were divided into two groups: the MSCs group received MSCs intravenously followed by coronary artery ligation (n = 22); the control group received MSCs intravenously followed by sham operation (n = 5). Mortality of the coronary artery ligation and sham procedure was 31.8% and 0%, respectively. Surviving animals (MSCs group, n = 15; control group, n = 5) were sacrificed at 1 day and 2, 4, 8, and 12 weeks after operation; thus 3 MSC and 1 control hearts were examined at each time point.

Tissue processing and staining for ß-galactosidase activity
On sacrifice of the recipient animals, blood, bone marrow, and hearts were collected. The blood samples were diluted sevenfold with Dulbecco’s Modified Eagle’s Medium containing 10% fetal bovine serum, plated in 35-mm dishes, and cultured for 2 weeks. Culture medium was changed twice a week, and most hematopoietic cells were discarded during this procedure. Bone MSCs were isolated from recipients’ femurs and tibias and then cultured for 1 week. Adherent cells derived from both the blood samples and bone marrow specimens were stained with X-gal staining solution as mentioned above. The hearts were rinsed with phosphate-buffered saline and perfusion fixed in 2% paraformaldehyde in phosphate-buffered saline. The staining for ß-galactosidase activity was performed as described above, but with the addition of 0.02% Nonidet P-40 and 0.01% deoxycholate to the staining solution [9]. After X-gal staining, the hearts were cut longitudinally and embedded in paraffin.

Histology and immunohistochemistry
Heart sections 5 µm in thickness were processed for either hematoxylin and eosin staining or immunohistochemical staining. Immunohistochemical staining was performed for anti- smooth muscle actin (Sigma Laboratories, St. Louis, MO), troponin I-C (Santa-Cruz Biotechnology Inc, Santa Cruz, CA), and sarcomeric myosin heavy chain molecules with MF20 as described previously [6, 9].

	Results

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Transfection efficiency and intravenous injection of mice marrow stromal cells
To trace the fate of mice MSCs after transplantation, we labeled them in vitro with a retrovirus carrying the LacZ gene. 5-Bromo-4-chloro-3-indoyl-ß-D-galactoside staining of these cells revealed nearly 100% of MSCs expressed ß-galactosidase activity (Fig 2A). We transplanted 6 x 10⁶ labeled mice MSCs intravenously into Lewis rats without immunosuppression. There was neither transplant-related mortalities nor morbidities associated with immunorejection. Bone marrow specimens of the recipient rats were collected at various intervals ranging from 1 to 13 weeks after transplantation. Labeled mice MSCs could be identified in the rat bone marrow specimens of both MSCs and control groups at all times studied (Fig 2B).

View larger version (80K): [in this window] [in a new window]   Fig 2. Histochemical staining for ß-galactosidase activity of mice marrow stromal cells in cultures. The transfected marrow stromal cells showed positive staining for ß-galactosidase activity (blue color). (A) Culture-expanded mice marrow stromal cells before implantation. (B) Bone marrow specimen of the recipient rat to which mice marrow stromal cells were transplanted intravenously 13 weeks before. LacZ+ mice marrow stromal cells (arrow) were identified, whereas host marrow stromal cells were unstained. (C) Blood sample obtained at 1 day after ligating the left coronary artery in rats to which mice marrow stromal cells were transplanted intravenously 1 week before the ligation. LacZ+ mice marrow stromal cells (arrows) were also identified, whereas host cells were unstained. (Original magnification [A through C], x100.)

View larger version (69K): [in this window] [in a new window]   Fig 3. Histochemical staining for ß-galactosidase activity of mice marrow stromal cells in the gross heart. Gross heart specimen of the recipient rat was harvested at 12 weeks after coronary artery ligation. Mice marrow stromal cells were transplanted intravenously 1 week before the ligation. After fixation, the heart was stained for ß-galactosidase activity of mice marrow stromal cells. Bluish discoloration can be seen on the infarcted myocardium, whereas noninfarcted myocardium remains unstained. (A) Frontal view. (B) Lateral view.

View larger version (103K): [in this window] [in a new window]   Fig 4. Histology and immunohistochemistry of the hearts with myocardial infarction. Mice marrow stromal cells were transplanted intravenously 1 week before coronary artery ligation. (A and B) Heart sample harvested at 8 weeks after ligation, and stained for ß-galactosidase activity and hematoxylin and eosin. Numerous mice marrow stromal cells were identified mostly in the infarcted myocardium. (C) Heart sample harvested at 1 day after ligation. LacZ+ mice marrow stromal cells (arrows) were seen near vessel (asterisk) in an intact area. (D) Heart sample harvested at 1 day after ligation. LacZ+ cell (arrow) was seen in the interstitium of an intact myocardium. (E) Heart sample harvested at 12 weeks after ligation. LacZ+ cell (arrow) was morphologically integrated into the scar formation. (F) Heart sample harvested at 12 weeks after ligation, and immunostained for -smooth muscle actin. LacZ+ cell (arrow) was seen in the vascular wall in the infarcted myocardium. (G) Heart sample harvested at 12 weeks after ligation, and immunostained for MF20. LacZ+ cells (arrows) had immunoreactivity for sarcomeric myosin heavy-chain molecules in their cytoplasms. (H) Heart sample harvested at 12 weeks after ligation, and immunostained for troponin I-C. LacZ+ cells (arrows) had immunoreactivity for troponin I-C in their cytoplasms. Original magnifications: (A) x100; (B) x200; (C through F) x400; (G and H) x1000.

Differentiation of mice marrow stromal cells in an infarcted myocardium
In the infarct scar area, some MSCs were seen in the fibrous layer. Morphologically, these MSCs had a myofibroblast-like appearance and may have contributed to scar formation (Fig 4E). Near the infarcted myocardium, there were areas of neoangiogenesis as could be expected after myocardial infarction. Some of this neovasculature contained labeled MSCs that expressed -smooth muscle actin in their cytoplasm, and some were integrated into vessel walls (Fig 4F). Moreover, some MSCs in the infarcted area stained positively for the sarcomeric myosin heavy chain (Fig 4G) and for the cardiomyocyte-specific protein, troponin I-C (Fig 4H). However, up until 2 weeks, the MSC-derived cells showed an immature appearance with a large nucleus to cytoplasm ratio and were negatively stained for these proteins.

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
In this study, we demonstrated that culture expanded xenogeneic MSCs were capable of homing into the bone marrow of immunocompetent adult recipients after systemic transplantation. The apparent lack of immune response indicated by the persistence of mice MSCs in the rats is intriguing. Although the murine MSCs have been reported to express major histocompatibility complex class I on their cell surfaces and lack class II [11], the tolerance of xenogeneic cells in a fully immunocompetent recipient is perplexing according to the classic self-non-self immune response paradigm of Burnet [12] and Billingham and colleagues [13]. Nevertheless, our findings could be consistent with the prediction of the more recent "danger" model of immune tolerance proposed by Matzinger [14] and Anderson and Matzinger [15]. This model posits that the antigen-presenting cells require the presence of "danger signals" as costimulant with the antigen to induce immune activation of T cells. Antigens presented without concomitant danger signal should result in tolerance. Thus minimal tissue damage associated with injection of mice MSCs in our experiments may have allowed for their survival. Recent in vitro and in vivo studies also reveal MSCs can exert multiple effects directly on the immune system [11], although precise mechanisms are still poorly understood. Most intriguing is the finding that MSCs can suppress the function of mature T cells, either directly or by stimulating suppressor T cells, and thus are tolerogenic. They also speculated that MSCs recruited to an area of tissue injury may downregulate inflammatory response to initiate tissue repair. But even if the MSCs are immune privileged, why do they not get rejected when they have differentiated? Perhaps by the time they differentiate, which may take several weeks, the danger signals from myocardial infarction have subsided. Clearly such speculations need to be confirmed by future studies. Nevertheless, the therapeutic importance of immunologic tolerance of adult stem cells cannot be overemphasized. This study demonstrated the tolerogenic properties of xenogeneic cells, and there is some evidence that allogeneic cells behave similarly [16]. The rationale for therapeutic cloning to obtain embryonic stem cells, a highly controversial issue, is to avoid immune rejection of these cells by the recipients. The reason for using autologous myoblasts and MSCs, which is currently undergoing early clinical trials, is that autologous cells can avoid immune rejection. However, use of autologous cells faces the disadvantages of a time lag between cell harvesting and implantation as well as the logistic complexity to transport them to and from a central laboratory for quality control and for isolation and expansion of donor cells. In contrast, use of tolerogenic allogeneic or xenogeneic adult stem cells will avoid the need for cloning, and frozen donor cells can be supplied to be readily available for clinical use without delay.

Another unique characteristic of MSCs is their capacity to migrate to an injured site in the body [17, 18]. To assess this capability in xenogeneic MSCs, we created myocardial infarction in rats by ligating the left coronary artery 1 week after mice MSCs had been intravenously transplanted. Although sham-operated hearts did not contain mice MSCs, the hearts with myocardial infarction had MSCs in the heart tissues. Interestingly, in the hearts harvested 1 day after coronary artery ligation, most of the labeled MSCs were found in the perivascular zone of noninfarcted myocardium, possibly because the coronary artery that supplied the infarcted area had been permanently occluded. However, in the hearts obtained after 2 weeks, most of the labeled MSCs were seen in the infarcted myocardium, suggesting they had migrated to the injured site. To further confirm our suggestion that these MSCs migrated from bone marrow to the heart through the bloodstream, we collected blood samples just before coronary artery ligation and 1 day and 2, 4, 8, and 12 weeks after coronary artery ligation. Mice MSCs could be detected only in the blood collected 1 day after ligation. Such findings appear to be consistent with the scenario that a signal or signals were released from the damaged tissue shortly after injury, initiating MSCs recruitment from the bone marrow and their migration to the injured area by way of the bloodstream.

To examine the normal physiologic response of MSCs to tissue injury in vivo, we did not artificially purify these cells to clonal subgroups before their transplantation in this study. Thus the multiple phenotypes expressed by these cells at the infarct sites may represent the existence of progenitor cells for different lineages in this cell population or the multipotential adult stem cells responding to different in situ signals in the microenvironment [17, 19].

Although the sample size of hearts examined at each point in this study is modest, it should be noted that experimental animals sacrificed at various times after myocardial infarction (n = 15) were all positive for implanted labeled cells without signs of rejection. When X-gal stain for ß-galactosidase is performed at a pH of 7.8 to 8.0 as described above [10], no false-positive stain of myocardial scar has been seen, not only in the 5 control animals in this study, but also in all sham-operated control animals in other series of experiments that we had previously reported [20].

In summary, our findings indicate that (1) xenogeneic MSCs can home in and survive in the bone marrow cavities of hosts without immunosuppression, (2) they are capable of being recruited to the injured myocardium through the bloodstream, and (3) they can differentiate into various phenotypes such as vascular smooth muscle cells and cardiomyocytes in the infarcted myocardium, resulting in a stable cardiac chimera without the need for immunosuppressive therapy. How such a chimera may affect cardiac function is an interesting and clinically relevant question that deserves further investigation.

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
We deeply appreciate the technical assistance of Minh Duong, BS.

	References

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