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. 2004 Jan 16;130(3):127–134. doi: 10.1007/s00432-003-0507-x

Hematopoietic stem cell transplantation: more than just hematopoietic?

Alexandros Spyridonidis 1,✉, Roland Mertelsmann 1, Jürgen Finke 1
PMCID: PMC12161821  PMID: 14727105

Abstract

A wealth of evidence has surfaced in the last three years to challenge age-old notions of stem cell compartments in mammalian adult tissues. It was only recently realised that large cellular infusions in clinical practice might contain stem cells with flexible fate potential. This review discusses the current status of the occurence of epithelial chimerism after hematopoietic cell transplantation and presents existing data on detection methodology, characteristics, underlying mechanisms, physiological implications and clinical significance.

Keywords: Keywords, Hematopoietic, Stem cell transplantation

Introduction

Allogeneic hematopoietic stem cell transplantation (HSCT) in humans results in true biological chimeras. Whereas circulating hematopoietic cells and their tissue derivatives, such as Kupffer cells in the liver (Gale et al. 1978), Langerhans cells in the skin (Volc-Platzer et al. 1984), and microglial cells in the brain (Unger et al. 1993), become donor genotype after transplantation, other cells were believed to remain recipient in origin. In line with this concept, Endler et al. in 1999 (Endler et al. 1999) assumed that the donor DNA material found in recipient buccal epithelial cells was due to hematopoietic “contaminants” in the purified epithelial cell population. However, studies in laboratory animals and in humans over the last several years indicate that HSCT generates unexpected populations in vivo, such as liver cells and other epithelial cells (references in Table 1).

Table 1.

Nonhematopoietic tissue chimerism after HSCT. (A animal, H human, BM bone marrow, BMsub bone marrow cell subsets, PBSC peripheral blood stem cells)

Donor cells Recipient Recipient organ References
Species Type Species Chimerism Functiona
A, H BM, PBSC, BMsub A, H Epithelium, liver + Petersen et al. 1999; Theise et al. 2000a; Theise et al. 2000b; Lagasse et al. 2000; Körbling et al. 2002
A, H BM, PBSZ, BMsub A, H Epithelium, colon ? Körbling et al. 2002; Okamoto et al. 2002; Spyridonidis et al. 2003
A, H BM, BMsub A Epithelium, pancreas + Hess et al. 2003
A, H BM, PBSZ, BMsub A, H Epithelium, skin, buccal ? Krause et al. 2001; Körbling et al. 2002; Tran et al. 2003
A BM, BMsub A, H Epithelium, lung ? Theise et al. 2002; Kotton et al. 2001; Suratt et al. 2003
A BM A Epithelium, kidney ? Poulsom et al. 2001
A, H BM, BMsub A, H endothelium, vessels, tumorvessels + Shi et al. 1998; Gunsilius et al. 2000; Lyden et al. 2001; Asahara et al. 1999; Grant et al. 2002; Kocher et al. 2001; De Palma et al. 2003
A, H BM A, H Osteoblasts, bone + Pereira et al. 1998; Horwitz et al. 1999
A, H BM A Chondrocytes, cartilage ? Pereira et al. 1998; Liechty et al. 2000
A BM, BMsub A Muscle, skeletal muscle, heart + Ferrari et al. 1998; Gussoni et al. 1999; Orlic et al. 2001
A BM A Neurones, CNS ? Eglitis et al. 1997; Brazelton et al. 2000; Mezey et al. 2000
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a+ denotes that BMT contributed to restoration of a damaged organ function. The references describing functional contribution of BMT are written in bold

Epithelial chimerism after HSCT. Is it real?

Documentation of epithelial chimerism (Fig. 1) after HSCT is typically done by demonstration that a single cell expresses both epithelial specific markers, most usually cytokeratins, and a donor-specific marker. Tracking of donor-derived cells after BMT typically involves the use of Y-chromosome analysis when male cells are introduced into female recipients, and green fluorescent protein (GFP) or β-galactosidase in laboratory animals. However, it became clear in recent years that microscopic examinations require caution. Initial reports in humans reporting conversions from hematopoietic cells into hepatocytes, skin cells, and epithelial cells of the gastrointestinal tract have been treated with scepticism because of methodological problems (Abkowitz et al. 2002; Holden et al. 2002). Lymphocytes entering the epithelial tissues via the circulation, might act as “contaminants” and can be easily mistaken as donor-derived epithelial cells if the expression of hematopoietic markers is not examined. In addition, the fact that tissue is a compact, three-dimensional (3D) structure has to be considered in the interpretation of results from microscopic examinations (Smallcombe et al. 2001). Overlapping cells can produce artefacts showing marker co-localisation which appears to be within the same cell although the markers are actually being expressed in different cells. Another potential problem in examining tissue chimerism in female patients by use of the Y-chromosome, is that Y-chromosome material has been found in maternal tissues from women having had a male fetus or after blood transfusions from male donors (Bianchi et al. 1996; Lee et al. 1999).

Fig. 1.

Fig. 1

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Epithelial chimerism after human HCT. A colon biopsy of a female patient having received an allogeneic BMT from a male donor was triple stained with fluorescence in situ hybridization for the visualization of the Y chromosome (red), fluorescent immunohistochemistry for cytokeratin (green), and TOTO-3 nuclear counterstain (blue). A donor-derived epithelial cell is seen

Although initial studies in humans suggesting the occurrence of epithelial chimerism after HSCT were not conclusive because of methodological limitations (Alison et al. 2000; Theise et al. 2000b; Körbling et al. 2002; Okamoto et al. 2002), the report of Lagasse et al. (Lagasse et al. 2000) in laboratory animals showing the generation of functional chimeric liver tissue after HSCT indicates in principle that this phenomenon can in fact occur. We recently performed a study in sex-mismatched HSC-transplanted patients by using strict criteria in the detection of epithelial chimerism (Spyridonidis et al. 2003). Attention has been paid to the technical aspects in order to be sure that the identified donor-derived cells express epithelial markers and are not “contaminating” hematopoietic cells. By using a 3D analysis on single sections of colon biopsies triple stained with donor-specific, epithelial-specific, and hematopoietic-specific markers we clearly demonstrated that epithelial chimerism after human HSCT is a real phenomenon. We excluded horizontal transfer as the underlying mechanism of our findings.

What are the patterns of epithelial chimerism after HSCT?

Data from animal and human reports imply the following characteristics of epithelial engraftment after HSCT:

  1. Rare event. Engraftment of epithelial tissue after HSCT has been documented as isolated single cells scattered throughout the epithelial tissue. Probably less than 1% of the overall tissue epithelial cells are BM-derived. The reported higher incidence of epithelial chimerism found in some human studies (up to 17% in the liver or 6% in the gastrointestinal tract) is most likely an artefact resulting from the enumeration not only of the donor-derived epithelial cells but also of the intraepithelial lymphocytes (Theise et al. 2000b; Körbling et al. 2002). Since no clusters of BM-derived epithelial cells have been found in human studies, most refer to this phenomenon as epithelial microchimerism. However, when environmental factors favour the survival and replication of these cells, as shown in HSC transplanted mice with liver failure due to tyrosinemia, substantial numbers of epithelial donor-derived cells may accumulate to become larger clusters (Lagasse et al. 2000).

  2. Universal event. To date the published scientific literature indicates that epithelial microchimerism after animal or human HSCT occurs in all transplanted recipients. Moreover, donor-derived epithelial cells have been found in all the epithelial tissues tested irrespective of the presence or absence of tissue damage. These include the liver, gastrointestinal tract, skin, oral cavity, lung, and kidney (see Table 1). Thus, it appears likely that epithelial microchimerism after HSCT is a universal event.

  3. Constant event. Epithelial microchimerism has been documented as early as 13 days and as late as 867 days after clinical HSCT (Körbling et al. 2002). Therefore, epithelial microchimerism appears not to be only a temporary phenomenon but rather a constant event. It is not clear whether the engraftment of epithelium is caused by lodging of donor-derived cells in the tissue at the time of intravenous injection or by endogenous seeding of cells from the engrafted bone marrow. In one study quantitative analysis showed a higher frequency of donor-derived epithelial cells in the sections taken a longer time after transplantation, favouring the latter hypothesis (Okamoto et al. 2002).

How does epithelial chimerism after HSCT occur?

The mechanisms underlying the occurrence of epithelial chimerism after HSCT are still unknown. Suggested theories are: fusion of donor hematopoietic cells with recipient epithelial cells, generation of epithelial cells from unknown epithelial precursors or universal stem cells residing in the bone marrow (BM) or transdifferentiation of hematopoietic cells.

Fusion of donor-derived hematopoietic cells with recipient epithelial cells?

Fusion between mammalian cells in vitro has been known for decades, and has been recently suggested to also occur between terminally differentiated cells and embryonic or adult BM cells (Terada et al. 2002; Ying et al. 2002; Spees et al. 2003). Experimental fusion of two distinct types of differentiated cells results in heterokaryons able to further divide and in which previously silent genes are induced to express (Blau et al. 1983 and 2002). Cell fusion has recently been shown to be the principal mechanism by which transplanted HSC generate chimeric livers in mice (Wang et al. 2003; Vassilopoulos et al. 2003). In humans, non-fusion mechanisms have been implicated in the generation of BM-derived buccal epithelial cells (Tran et al. 2003).

Generation of epithelial cells from tissue specific progenitors in bone marrow?

Bone marrow (BM) is a heterogeneous tissue and appears to contain various types of cells. Avital et al. (Avital et al. 2001) found that mouse β2m–/Thy-1+ BM cells express albumin-, HNF-4-, C/Eba-, and CYP3A2-mRNA corresponding to a hepatocyte stem cell-like phenotype. By using retroviral marking, Verfaillie’s group (Jiang et al. 2002) recently demonstrated that a single postnatal mouse, rat or human BM stroma cell, called a “multipotent adult progenitor cell” (MAPC), can differentiate in vitro into cells with endothelial, neuroectodermal or hepatocyte phenotype and function. However, the possibility that this MAPC is the result of “dedifferentiation” of a bona fide hematopoietic stem cell within the culture system cannot be excluded. The fact that epithelial microchimerism is also seen after peripheral blood stem cell transplantation argues against the stroma-derived pluripotent stem cell hypothesis, although a co-mobilization of stromal precursors cannot be excluded (Huss et al. 2000; Zvaifler et al. 2000).

Generation of epithelial cells from universal stem cells?

It may be speculated that a universal type of stem cell, akin to an embryonic stem cell, exists in adult BM. However, such totipotent cells in healthy adult organisms have been found only in metazoans to date. In planaria, a simple worm, totipotent cells are distributed throughout the parenchyma and can differentiate and regenerate lost body parts (Newmark et al. 2002). By contrast, the regenerative capabilities observed in some vertebrates, for example urodele amphibians, are not based on pre-existing undifferentiated cells but on the ability of terminally differentiated cells to transdifferentiate (Brockes et al. 1997).

Transdifferentiation of hematopoietic cells?

“Dolly”, the cloned sheep, provides a clear example showing that shut-off genes in differentiated adult mammalian cells can be reawakened (Wilmut et al. 1996). This indicates that the differentiated state of adult mammalian cells is neither fixed nor irreversible. Can the observed epithelial chimerism after BMT be explained by transdifferentiation of hematopoietic cells?

Data from bone marrow transplantation experiments

The conclusion that transdifferentiation in vivo has happened is usually based on the transplantation of a well-characterized, highly purified cell population and the detection of tissue chimerism. Following transplantation of 2,000–5,000 highly purified male murine HSC into irradiated female mdx mice, the mouse model of Duchenne muscular dystrophy, Gussoni et al. (1999) found male muscle cells producing the missing dystrophin protein. Krause et al. (Krause et al. 2001) transplanted single cells—as determined by limiting dilution—in a murine hematopoietic transplantation assay and documented engraftment in different epithelial tissues 11 months later. Lagasse et al. (Lagasse et al. 2000) regenerated damaged liver by transplantation of as few as 50 purified c-kit+ ThylowLin-Sca-1+ HSC. Whereas these data are to different degrees suggestive of in vivo transdifferentiation events, they are not conclusive since the possibility remains that the unexpected epithelial cells apparently generated by purified HSC were due to contaminants in the purified or enriched cell population. To examine this, Wagers et al. (Wagers et al. 2001) transplanted a single c-kit+ThyloLin-Sca-1+ in mice and could not find any robust transdifferentiation.

Evidence for transdifferentiation of terminally differentiated adult cells

That differentiated adult cells can change their fate is illustrated by examples from the world of lower vertebrates and by experimental manipulations of mammalian cells. During limb regeneration in urodele amphibians, terminally differentiated cells “redifferentiate” and form a new limb (Brockes et al. 1997). Terminally differentiated mammalian myocytes (Odelberg et al. 2000) or oligodendrocytes (Kondo et al. 2000) have been induced to “transdifferentiate” in vitro into stem cells capable of re-differentiating into different cell types. Pancreas cells can be converted in vitro into liver cells (Shen et al. 2000), and fibroblasts can transdifferentiate into myoblasts and retinal epithelial cells (Choi et al. 1990). Lymphocytes with rearranged DNA have been shown to change to macrophages and granulocytes (Borzillo et al. 1990; Lindeman et al. 1994; Montecino et al. 2001). Currently, we can only speculate about the mechanisms involved in such dramatic changes in cell fate:

  1. The role of the microenvironment. The recent work of Spradling et al. addressed the role of stem cell niches on a stem cell’s function by using an in vivo model in Drosophila ovary. The authors found that the niche environment may constitute a primary regulatory force that may be capable of reprogramming somatic cells to become stem cells (Spradling et al. 2001; Xie et al. 2000). The early murine embryo provides a suitable environment for the transdifferentiation of cells as demonstrated by the development of chimeric mice after injection of adult stem cells in the murine blastocyst (Geiger et al. 1998). The role of the microenviroment in the cell fate is underlined also in the recently proposed “Chiarascuro” stem cell model (Quesenberry et al. 2002). Rather than a hierarchical structure of the hematopoietic (or other) system, this model suggests a very flexible system in which phenotypic shifts, probably also from hematopoietic to epithelial, could sequentially occur depending on cell cycle phase and specific microenviroment.

  2. The role of the macroenvironment. In order to change its fate, a stem cell presumably responds to key migration factors and growth factors. An example of this is the role of hepatocyte growth factor in the circulation during liver tissue repair (Moolten et al. 1967), or the role of G-CSF in hematopoietic stem cell mobilization. McGann et al. (McGann et al. 2001) could more directly show that humoral factors induce mammalian cells to transdifferentiate. A protein-rich extract derived from newt regenerating limbs was able to dedifferentiate terminally differentiated mouse C2C12 myotubes in vitro. It is likely that factors released by damage may induce stem cells to home to a particular tissue and change cell fate.

  3. Intrinsic features of cells. In order to respond to transdifferentiating signals, cells have to express specific receptors and/or signaling molecules. Ectopic overexpression of MyoD in C3H10T1/2 fibroblasts or of the homeobox-containing transcriptional repressor msx-1 in C2C12 myotubes initiated a transdifferentiation program in these cells (Odelberg et al. 2000). The expression of CCAAT/enhancer-binding protein β (C/EBPβ) was found to be crucial during transdifferentiation of pancreatic into hepatic cells (Shen et al. 2000). When B lymphoid differentiation is blocked by ablation of Pax5, B cell progenitors are able to differentiate into a wide range of other hematopoietic cell types (Graf 2002). Nuclei of adult mouse thymocytes and of adult human blood lymphocytes are induced to strongly express oct-4 when injected into Xenopus oocytes (Byrne et al. 2003). As we learn more about the genes expressed in cells changing fates, we may elucidate the regulatory mechanisms involved in plasticity and/or transdifferentiation.

What are the physiological and clinical implications of epithelial chimerism after HSCT?

Whether epithelial microchimerism after human HSCT is an incidental by-product of the transplantation without ancillary biological significance or whether it has clinical consequences and/or therapeutic implications is still unknown. Data exists to date only in animal models.

Are there clinical consequences of epithelial microchimerism after HSCT?

Since epithelial chimerism is a rare event and occurs only focally it may be speculated that it cannot interfere with organ function. However, parenchymal microchimerism has been implicated in the pathogenesis of various diseases in humans. Microchimerism of maternal tissues with fetal cells has been associated with autoimmune diseases such as scleroderma (Nelson et al. 1999), thyroid disease (Srivatsa et al. 2001) or liver disease (Jones et al. 2000); the degree of endothelial chimerism in human kidney allografts was correlated with vascular rejection (Lagaaij et al. 2001); intragraft hepatocyte or pneumocyte chimerism after liver or lung transplantation has been correlated with recurrent hepatitis or chronic lung injury, respectively (Kleeberger et al. 2002 and 2003). Whether these isolated single epithelial cells found to be scattered throughout the tissue directly influence organ function or whether their presence is simply indicative of impaired function is not yet known. In the setting of BMT, it will be interesting to find out if there is any correlation between the occurrence of epithelial microchimerism and organ damage or graft versus host disease.

Non-hematopoietic tissue repair with HSCT? How?

Reversion of autoimmunity

HSCT may positively affect epithelial organ function by reversing autoimmune processes which destroy the organ. Animal data and observation in humans indicate that autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Crohn’s disease, alopecia universalis, chronic glomerulonephritis or autoimmune diabetes Type I may be resolved after HSCT (Kreisel et al. 2003; Feher et al. 2002; Mathieu et al. 1995).

Generation of functional non-hematopoietic tissue after HSCT?

The finding that transplanted BM is involved in the generation of epithelial cells raises the question of whether BMT could functionally contribute to tissue repair by replacing damaged epithelia. BM-derived liver cells, pneumocytes, and kidney tubular epithelial cells in mice were found to express mRNA-albumin, mRNA-surfactant B, and a specific cytochrome P450 enzyme (CYP1A2), respectively, indicating an appropriate functional capability in the engrafted cells (Theise et al. 2000a; Krause et al. 2001; Poulsom et al. 2001). However, since these cells occur as isolated single cells, it seems unlikely that, at least in the setting of clinical HCT, they play a role in the homeostasis, regeneration, and function of epithelial tissue. However, there may be factors, both in the graft and in the recipient, that favor the survival, the replication, and the functional properties of these cells. Perhaps the most robust and well-defined demonstration of the generation of functional nonhematopoietic tissue from transplanted HSC so far is the study by Lagasse et al. (Lagasse et al. 2000). The authors transplanted wild-type HSC into irradiated FAH-/- mice, a model of fatal-hereditary tyrosinemia type I liver disease. The HSCT resulted in liver regeneration and restoration of multiple liver functions to near wild-type levels leading to long-term survival. The prinicipal mechanism by which HSCT regenerated liver mass and liver function was found to be cell fusion between hematopoietic cells and host hepatocytes (Wang et al. 2003; Vassilopoulos et al. 2003). Kinetic studies of the liver regeneration in this model indicated that the single “fused” cells first detected 7 weeks post-transplant expanded in vivo, generating by 7 months post-transplant a functional population accounting 30–50% of the liver mass (Wang et al. 2002). Thus, in this model BM cells were directly involved in the generation of new hepatocytes, which were able to rescue the mice from an otherwise lethal disease.

“Bystander effect” of transplanted hematopoietic stem cells on tissue regeneration?

The surge in experiments in laboratory animals done in recent years aiming at the analysis of epithelial chimerism after BMT brought to light an interesting observation: BMT may indeed contribute to non-hematopoietic tissue regeneration and the restoration of damaged organ function. However, accumulating evidence suggests that BM cells do not directly replace damaged epithelial cells but they initiate regenerative processes from endogenous tissue cells. Hess et al. (Hess et al. 2003) could restore damaged pancreatic function of streptozotocin treated mice by BMT. Interestingly, pancreas regeneration and reversal of hypoinsulinemia was observed only after transplantation of c-kit+ BM stem cells, but not from c-kit negative cells. Although the authors could clearly demonstrate the generation of BM-derived insulin producing pancreatic cells, they showed that these cells did not, in themselves, functionally rescue the recipients but that the BMT with c-kit+ cells initiated the proliferation of endogenous pancreatic cells. By which mechanisms BM stem cells initiate endogenous tissue repair processes is not yet known. Whether the BM-derived insulin producing pancreatic cells or other, as yet unknown, BM-cell subsets are involved in the initiation of the endogenous pancreas regeneration has to be defined. The fact that BM-derived epithelial cells were found mainly in regenerated pancreas and to a much lesser degree in organs with no signs of regeneration makes the first possibility very likely. On the other hand, the restorative process may be mediated through induction of neovascularization from BM-derived cells. Endothelial progenitor cells and cells with proangiogenic activities have been identified in the BM and have been found to functionally contribute to neovascularization during wound healing, limb ischemia, endothelialization of vascular grafts, retinal regeneration, and tumour growth (review Rafii et al. 2003 and references Table 1). Independently of the mechanisms and the type of BM-cells involved (BM-derived epithelial or endothelial cells), induction of endogenous tissue repair by transplantation of BM stem cells might also explain the improvement of post-infarct cardiac function in laboratory animals (Orlic et al. 2001) and the decrease of bone fracture frequency in patients with osteogenesis imperfecta (Horwitz et al. 1999), despite the very low frequency of donor-derived cardiomyocytes and osteoblasts, respectively, which were found.

Conclusion

Although BMT has been a part of clinical practice for more than 30 years, it was only recently realised that BMT results not only in replacement of the lymphohematopoietic system but also in generation of non-hematopoietic cell populations. More suprising is the accumulating evidence that BMT can contribute to non-hematopoietic tissue regeneration and restoration of damaged organ function. The initial steps toward understanding that hematopoietic stem cell transplantation involves more than just the hematopoietic system have been done. Many issues remain to be addressed. A new era of intensive research has been opened for both stem cell biologists and clinicians.

Footnotes

A. Spyridonidis is supported by grant from the Landesstiftung Baden Württemberg

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