(Journal of Leukocyte Biology. 2005;78:836-844.)
© 2005
by Society for Leukocyte Biology
Postnatal stem cell survival: does the niche, a rare harbor where to resist the ebb tide of differentiation, also provide lineage-specific instructions?
Vincent Kindler1
Hematology Service, Geneva University Hospital, Switzerland
1Correspondence: Hematology Service, Geneva University Hospital, 25, Micheli-du-Crest, 1211 Geneva 14, Switzerland. E-mail: vincent.kindler{at}hcuge.ch
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ABSTRACT
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Postnatal stem cells regulate the homeostasis of the majority of our tissues. They continuously generate new progenitors and mature, functional cells to replace old cells, which cannot assume the tissue function anymore and are eliminated. Blood, skin, gut mucosa, muscle, cartilage, nerves, cornea, retina, liver, and many other structures are regulated by stem cells. As a result of their ability to produce large numbers of functionally mature cells, postnatal stem cells represent a promising tool for regenerative therapy. Indeed, unmanipulated stem cells or their progeny amplified in vitro are already used in some clinical applications to restore the function of injured or genetically deficient tissues. However, despite our cumulating understanding concerning postnatal stem cells, many aspects of their functionality remain unclear. For instance, in most tissues, we cannot reliably define the phenotype of the postnatal stem cells sustaining its survival. We do not know to which extent the environment surrounding the stem cell—the niche—which is a key actor insuring stem cell self-maintenance, is also implicated in the maintenance of stem cell lineage specificity. Moreover, we have to clarify whether postnatal stem cells are capable of undertaking "transdifferentiation", that is, the conversion of one cell type into another under physiological conditions. Answering these questions should help us to draw a more accurate picture of postnatal stem cell biology and should lead to the design of safe, effective therapies.
Key Words: self-maintenance • transdifferentiation • nuclear reprogrammation • regenerative therapy
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STEM CELL PHYSIOLOGY: AN OVERVIEW
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Self-maintenance and tissue homeostasis
Most tissues of the organism are remodeled constantly. Old cells, which exhibit declining biological functions, are removed by apoptosis and replaced by newly differentiated cells. Freshly differentiated cells are thought to be derived from "stem cells", resident in a specific cellular environment called the niches, which provide the adhesive support to maintain the stem cells within the tissue and the factors needed to insure the balance between the output of mature cells and the maintenance of the stem cells [1
, 2
].
It is generally accepted that stem cells are mostly dormant in the G0 stage [3
] and that only few stem cells at the time supply all the cells necessary for the maintenance of the tissue. Stem cells are able to undertake iterative cell cycles without alterations, generating after each cell division one daughter stem cell identical to the mother cell and one daughter "transit" stem cell, which has lost its ability to proliferate forever [4
]. Such a process is referred as "asymmetric cell division", as the two daughter cells do not display identical characteristics. The decision of each daughter cell to self-maintain or to differentiate is a stochastic process [5
, 6
]. The probability of stem cell self-maintenance, i.e., the probability that a stem cell will generate one stem cell per mitosis, is p(sm) = 0.5 to insure tissue homeostasis. No evidence demonstrating that each stem cell of a given tissue proceeds to asymmetrical divisions exists, but the model holds true for a steady-state and a long-lived tissue: No matter how the flux of ancestral and transit stem cells occurs, the tissue volume is maintained, indicating that the stem cell number remains constant. Should this number vary, the tissue would die rapidly or conversely, become hyperplasic. The transit stem cell will proliferate on a finite basis but most often, in a symmetrical manner, giving birth after few cell cycles to a multitude of transit stem cells, which will eventually differentiate into one or several lineages of mature (nondividing), functional cells. According to this scheme, the number of stem cells remains constant (stem cells are self-maintaining), and large numbers of differentiated cells that will constitute tissues are generated. In certain instances, i.e., when a major injury induces a large depletion of the stem cell compartment, transit stem cells immediately derived from the primordial stem cell can revert to an ancestral stem cell phenotype to insure tissue regeneration. Transit stem cells in the injured tissue have to increase transiently their p(sm) to a value >0.5 to insure stem cell amplification and tissue regeneration. The mechanisms allowing transit stem cells to express the ancestral stem cell phenotype in emergency situations are not known, but the vacancy of the stem cell niches, consecutive to ancestral stem cell destruction, may represent the main stimulus inducing transit stem cells to revert their phenotype (see below).
Thus, stem cells are tightly controlled in normal tissue and harbor many mechanisms protecting their genome from mutation [7
]. However, despite such protection, in some rare instances, stem cells may become cancerous. This situation is best illustrated in chronic myeloid leukemia, whereby all malignant blood cells, irrespective of their lineage, express an identical chromosomal translocation inherited from the malignant hematopoietic stem cell (HSC) [8
].
Importance of the niche: the hematopoietic example
The self-maintenance of stem cells is secured only if the appropriate microenvironment—the niche—is present. The cross-talk of the stem cell with its niche involves numerous mediators. Among the different tissues harboring stem cells, the bone marrow, which is the major site of hematopoiesis in the adults, is the best understood. In this tissue, two distinct areas have been identified: the osteoblastic niche, where the HSC are in close contact with the osteoblasts and remain quiescent, and the vascular niche, closer to the center of the medullar cavities where HSC divide to produce transit stem cells (for review, see ref. [9
]). Niche cells and HSC cross-talk via membrane-bound and soluble molecules controlling stem cell homing and immobilization as well as stem cell survival and self-maintenance. Soluble chemokines, such as stroma-derived factor 1 (SDF-1), secreted by the osteoblasts, attract and immobilize the HSC, which express the SDF-1 receptor CXC chemokine receptor 4 (CXCR4) [10
, 11
]. CXCR4/SDF-1 seems to play a pivotal role in hematopoiesis, as mice knockout for these genes die in utero and exhibit a profound decrease of HSC number in the bone marrow (BM) [12
]. Soluble hematopoietic growth factors, most probably trapped within the extracellular matrix such as interleukin (IL)-7, and membrane-bound hematopoietic growth factors, including stem cell factor (SCF) and fetal liver tyrosine kinase 3 ligand (FLT3L), which are synthesized by osteoblasts, insure cell survival [13
14
15
]. Soluble and membrane-bound factors such as Tie-2 and osteopontin (after its activation by thrombin) control the self-maintenance of stem cells by blocking their differentiation in the niche [14
, 16
, 17
]. Finally, membrane-bound molecules, including factors initially identified as key regulators of embryogenesis such as Wnt [18
, 19
] and Notch ligand Jagged-1, are expressed on osteoblasts and interact with their respective ligands Frizzled and Notch on HSC to inhibit their differentiation and insure their self-maintenance [20
21
22
].
The signals generated by the niche induce intracellular messengers in stem cells whose final targets are the regulators of DNA accessibility and transcription. For example, DNA binding factors, which were first recognized for their involvement in embryonic development, are key actors regulating HSC maintenance or differentiation (for details, see ref. [23
]). Polycomb genes (Pc-G), which are expressed early in embryogenesis [24
], are expressed at increasing levels as cells get more differentiated [25
]. Pc-G are, with the exception of the BM-1 gene, transcriptional repressors. They interact with the chromatin as heterogeneous, multimeric complexes [26
]. The interaction of the Pc-G proteins with their response element locally compacts the chromatin and forbids transcriptional factors to access the DNA [27
]. The Pc-G protein complexes target a family of genes, which was also originally identified in early embryo development: the homeobox (Hox) genes. Accordingly, and in contrast with the Pc-G, Hox genes are highly expressed in HSC, and their expression decreases as cells commit to a specific lineage [28
]. Hox genes can be subdivided in four clusters, A, B, C, and D, which localize on chromosomes 7, 17, 12, and 2, respectively [29
]. Hox genes from clusters A and B are detectable in HSC, and Hox A genes segregate with myeloid and Hox B genes, with erythroid progenitors once cells undertake differentiation [30
]. The expression of these genes is virtually extinguished in fully differentiated leukocytes [28
]. Another family of Hox genes, the Pax genes, also exhibits a highly restricted expression related to the state of cell differentiation. Of interest, Pax5 expression is absolutely required for HSC differentiation into B lymphocytes, and Pax5-defficient mice are devoid of such cells. By contrast, all other hematopoietic lineages are represented normally in these mice, underlining the specificity of the Pax5-controlled differentiation process [31
].
The extensive self-maintenance of HSC also involves the telomerase, which regenerates the repetitive telomeric DNA that is lost after each chromosomal duplication. This enzyme is associated with unlimited proliferative potential and is found in germ-line cells and in immortalized tumor cell lines [32
33
34
]. Telomerase expression decreases as HSC differentiate but is reactivated once normal differentiated T and B lymphocytes undertake clonal expansion after an antigenic stimulus [35
].
Thus, the mechanisms controlling stem cell maintenance are numerous and represent a complex network involving intra- and extracellular signals. Moreover, new molecules are constantly identified, emphasizing the complexity of the niche-stem cell interaction.
Can we identify stem cells?
Stem cells are difficult to define and recognize morphologically, as they are few within a tissue, and they do not express the features of the terminally differentiated cells. In addition, they are most often identified at posteriori by their function, i.e., their ability to generate a progeny that insures tissue homeostasis or regeneration. Thus, stem cell assays are conducted in conditions mimicking stress situations. HSC or mesenchymal stem cell (MSC) presence is assessed by the progeny recovered after forced in vitro amplification and/or differentiation in conditions lacking most, if not all, of the constituents of the niche. Even in vivo assays, which consist of the injection of cells into a conditioned or deficient host, represent a stress situation that may not, if the host is xenogenic, provide an appropriate niche. Such manipulations will most probably alter the original properties of the stem cell. This fact is best described by Potten and Loeffler [4
] who wrote: "... to answer the question whether a cell is a stem cell we have to alter its circumstances and in doing so inevitably lose the original cell and in addition we may only see a limited spectrum of response. This situation has a marked analogy with Heisenberg’s uncertainty principle in quantic physics."
Although in some circumstances, stem cells can be associated with one phenotype, they generally display heterogeneous surface markers. For instance, the coexpression of Sca-1 and CD34 on murine hematopoietic cells and the expression of CD34 on human hematopoietic cells determine a population enriched in HSC [36
, 37
]. However, CD34+CD38– cells, but also CD34+lin– cells, CD34+Hoechstlow cells, or even CD34– cells, have been reported as being "true HSC", capable of reconstituting a host with a much higher efficiency than plain CD34+ cells [38
, 39
]. The issue is further complicated by the salient observation that neither the phenotype nor the ability of HSC to reconstitute the host is stable throughout the HSC cell cycle [38
].
The MSC phenotype is also a source of controversy. The association of STRO-1 expression with ex vivo MSC observed by some authors [40
] has been challenged by others [41
]. Moreover, the culture conditions, the culture duration, and the cell density influence the phenotype and the cell self-maintaining potential. High-density cultures seem to favor the generation of MSC, which are phenotypically and morphologically homogenous but are suspected to induce a loss of the multipotent progenitors [40
, 42
43
44
]. Similar observations have been done in other studies aimed at the detection of multipotent adult progenitor cells (MAPC) [45
]. As for HSC, no firm evidence concerning the stemness of the cells could be established from MSC and MAPC ex vivo or in vitro phenotype, and more of a concern, in vitro manipulations may alter the function of the cells.
Collectively, these observations suggest that the stemness of a cell may vary according to its physiological status (i.e., its current pattern of gene expression) and/or its environment. It may therefore be more realistic to define stemness as a state rather than an entity, which might be, as suggest by Zipori [46
], "a transient and reversible trait that almost any cell can assume given the correct trigger (niche) and that is characterized by having many potential outcomes but no specialization". This could explain why, despite the intense activity focused on the identification of a postnatal stem cell phenotype, its definition remains elusive in most tissues investigated.
Definition of a "clinically functional" stem cell
Most primary cells that are neither tumorigenic nor transformed by a virus or an exogenous transgene do not proliferate forever in vitro. This is the case for MSC and HSC, and in this regard, they should not be considered as stem cells. However, the restricted, proliferative potential observed in vitro may not be representative of stemness incapacity but more likely of the absence of physiological niches allowing self-maintenance [1
].
The incertitude concerning the stemness of a cell population may not harness its clinical use, as the stemness of certain cells may be unveiled in vivo only, and in many cases, ancestral stem cells may not be required for therapeutic applications. Aside hematopoietic reconstitution, which requires life-long self-maintaining stem cells from exogenous origin, many regenerative therapies, such as bone healing or cardiac tissue regeneration, may be fulfilled by transit stem cells, whose temporary help will be sufficient to insure short-term tissue reconstitution before stem cells, regenerated from the recipient, take over long-term tissue homeostasis. Thus, only clinical experimentation can tell whether a true, self-maintaining stem cell is absolutely required for a specific treatment or whether a transit stem cell, which will function as a "therapeutic stem cell", is sufficient.
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POSTNATAL STEM CELLS AT WORK: FEW EXAMPLES
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Epithelial stem cells (ESC)
ESC are present in organs and tissues that exhibit diverse morphologies and functions. The skin, which represents the first barrier against microorganisms; the cornea, which diffracts light; and the liver, which allows the inactivation of toxins via multiple biochemical processes, are mostly composed of epithelial cells. Stem cells from these sources can be amplified in vitro to reconstitute injured or genetically deficient tissues.
In the skin
The skin comprises three types of stem cells: the hair follicle stem cell, the upper outer root sheath stem cell, and the interfollicular epidermal stem cell. The hair follicle stem cells are the most ancestral, as they are able to regenerate the basal layer of the epithelium, the hair follicle, and the sebaceous glands [47
, 48
]. They are used to produce in vitro large surfaces of epithelium, which allows the reconstruction of the skin of patients suffering from severe burns or ulcers [49
].
In the cornea
The corneal epithelium is maintained by a population of stem cells residing in an annular area called the "limbus", which encircles the cornea with its inner border and faces the conjunctiva with its outer border. The limbal basement membrane provides resident stem cells with an adherence niche protecting them from injury and movement within their microenvironment [50
, 51
]. A deficit in limbal stem cells induces the invasion of the cornea by the neighboring conjunctival epithelium, which is not able to differentiate into transparent epithelium, and corneal keratinization, poor vision, and vascularization ensue [51
]. The autologous transfer of a multilayer epithelium obtained after amplification of limbal stem cell in vitro is used for grafting patients with unilateral limbal stem cell deficiency [52
]. This technique produces significant improvements in corneal clarity and surface stability.
In the liver
The liver stem cells comprise the hepatocytes and the bile ductal cells. In response to parenchymal loss, hepatocytes normally restore the liver [53
]. However, when a massive damage occurs, or when the regeneration potential of the hepatocytes is altered, the regenerative process is undertaken by the bile ductal oval cells, which differentiate into hepatocytes [54
]. Unmanipulated hepatocyte suspensions injected into children with inborn errors of liver metabolism restore the hepatic function [55
56
57
], but such a procedure requires up to 2 billion primary cells, a number that is not easily available. Hopefully, in vitro-amplified hepatocytes from small-sized biopsies seem to display similar properties than ex vivo specimens and could be used as a surrogate source [58
].
HSC
Blood cell formation relies on a limited pool of cells localized in the BM, which insures full recovery of hematopoiesis when injected into a lethally irradiated host [59
]. For this reason, the BM has been used as the primary source of HSC to restore the hematopoiesis of leukemic or cancerous patients lethally conditioned by total body irradiation [36
, 37
]. However, BM harvesting is a rather painful process, and now HSC are essentially recovered from the blood of donors mobilized with granulocyte-colony stimulating factor (G-CSF). Human CD34+CD45+ cell suspensions, although certainly comprising cells that are not stem per se (see previous section about stem cell identification), contain enough stem cells to insure a full, life-long recovery of hematopoiesis in lethally conditioned recipients, and the number of CD34+ cells grafted into aplastic patients correlates inversely with the delay of hematopoietic restoration [60
]. Indeed, grafting CD34+ cell numbers inferior to 106 cells/kg of the recipient body weight generally leads to graft failure. Thus, human CD34+ cell suspensions correspond to the clinical definition of a therapeutic stem cell.
In vitro differentiation of HSC to generate therapeutic cells
Culture of CD34+ cells from cord blood with hematopoietic growth factors such as FLT3L, thrombopoietin (TPO), and SCF allows the extensive amplification of hematopoietic progenitors [61
] that exhibit the ability to generate megakaryocytes, erythroids, granulocytes, monocytes, macrophages, and myeloid dendritc cells (DC) when further cultured with lineage-specific factors. These differentiated cells are phenotypically and morphologically similar to in vivo-differentiated cells [62
] (Fig. 1
) and could be used for regenerative therapy. However, it is difficult to generate large numbers of these cells in vitro under good laboratory practices, as bovine serum is almost always included in the cultures. So far, only myeloid DC have been evaluated in immunotherapies aimed at the eradication of leukemic or melanoma cells via the generation of tumor-specific cytotoxic T lymphocytes [63
, 64
].
MSC
MSC were first identified by Friedenstein and co-workers [65
, 66
], who observed that the BM stroma contained osteogenic progenitors that expanded clonally in vitro and formed colonies of different size and density, presumably composed of several mesenchymal lineages. Subsequently, many authors explored the biology of the MSC, uncovering their ability to differentiate into various lineages [67
, 68
] and identifying new sources such as skin, adipose tissue, and nonhematopoietic BM trabecular bone [69
70
71
72
]. In 1999, Pittenger et al. [43
] were the first to describe rigorously defined cell culture conditions that would differentiate MSC clones into several distinct cell lineages.
Clinical use
MSC are already used in few examples of regenerative and immunomodulatory therapies in humans [73
, 74
]. MSC amplified in vitro, used "as such" or after differentiation, can participate in tissue regeneration after acute or chronic injury [75
]. MSC may also facilitate HSC grafting by reconstituting the medullar environment necessary for the correct homing of the grafted hematopoietic cells and the start-up of hematopoiesis [76
]. In addition, in allografting situations, MSC, as a result of their immunotolerizing properties, increase graft survival and decrease graft-versus-host disease (GVHD) [74
, 77
, 78
]. MSC have been used with success on a 9-year-old boy grafted with allogenic HSC who could not overtake grade IV GVHD despite a heavy follow-up with chemical immunosuppressors and who was rescued by two infusions of maternal MSC amplified in vitro [74
].
Alternatively, MSC could be modified genetically before injection into the host and used as an in vivo depository of engineered transgenes to correct the host genetic defect. MSC transduced with erythropoietin or factor IX have been reported to secrete the corresponding proteins for up to 90 days after subcutaneous injection into baboons [79
80
81
].
Altogether, these data strongly suggest that MSC will be used at an increased frequency in future therapies.
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TRANSDIFFERENTIATION: WHERE IS THE REALITY?
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Until recently, postnatal stem cells were thought to be tissue-specific. However, several studies claimed that such cells, once injected into a host, could undertake "transdifferentiation", a biological process defined as "the ability of adult stem cells to cross lineage barriers and adapt the expression profile and functional phenotype of cells that are unique for other tissues" [82
]. Despite the extensive excitement generated by this finding, the observation was not new. In 1973, Eguchi and Okada [83
] reported that single cells isolated from the pigmented retinal epithelium of chick embryo permuted to unpigmented lens cells forming "lentoid" bodies after clonal amplification, demonstrating that cells originating from one tissue could differentiate into another one [83
]. According to this original observation, transdifferentiation implies that there is a lineage relationship between the initial and the transdifferentiated cells (i.e., both were of epithelial origin here) and that the transdifferentiated cell acquires the function of the new tissue.
Transdifferentiation "à la mode" postnatal stem cells was initially based on observations describing that plain BM cells or peripheral blood white cells collected after G-CSF perfusion of the donor could engraft into other tissues and acquire the phenotype of these tissues. For instance, hepatocytes and epithelial cells expressing the y chromosome of the donor have been identified in lethally conditioned (human) patients reconstituted with sex-mismatched HSC [84
], and suspensions of autologous HSC mobilized with G-CSF rescued an experimentally infarcted heart by promoting myocardial regeneration [85
]. The transdifferentiation of neural stem cells into blood cells in vivo has also been reported [86
]. Although many of these original studies suggested that transdifferentiation occurred after postnatal stem cell injection into an injured host, none of them rigorously demonstrated the process. Such studies were not designed to investigate clonal differentiation (with one exception; see below) nor did they assess the function of the transdifferentiated cells. Many methodologies used in these studies were inadequate and led to a false positive [87
]. Cell fusion or cell superposition was often responsible for the apparent transdifferentiation observed [88
, 89
], and cell function was hardly assessed [90
]. Moreover, recently, carefully controlled, in vivo experiments undertaken with lethally irradiated rats and mice, reconstituted with HSC from appropriate donors, clearly demonstrated that these cells did not participate in liver regeneration if this organ were injured after HSC grafting [91
, 92
]. By contrast, the work of Krause et al. [93
] showed that mice reconstituted with one single HSC exhibited, in various organs, lineage-specific cells that derived from the donor HSC. This study was by definition clonal and undoubtedly demonstrated that multilineage differentiation occurred after HSC injection, but one can wonder, as a result of the difficulty in identifying stem cells (see previous sections), whether the cell injected was really a HSC or whether it consisted of a more primordial cell with a broader array of differentiation. Cells such as the hemangioblast, which gives birth to hematopoietic and endothelial cells [94
]; the mesodermal stem cell, which differentiates into all the mesenchymal lineages plus endothelial cells; or the MAPC, which differentiates into mesenchymal cells, and cells with characteristics of visceral mesoderm, neuroectoderm, and endoderm in vitro have been identified and support this hypothesis [45
, 95
]. One may expect that such cells, if present within hematopoietic cell suspensions, could be responsible for the apparent transdifferentiation actually attributed to bona fide lineage-restricted HSC.
Recently, an alternative process to HSC transdifferentiation, which could also explain the above results, has been proposed in two studies [96
, 97
]. These authors showed that nonhematopoietic tissue-committed stem cells (TCSC) were circulating in the blood and were attracted into the BM by the SDF-1, thus indicating that the BM was a privileged "hideout" place for postnatal stem cells of various specificities, already committed to a lineage. Such TCSC could be mobilized from the BM into the circulation after systemic perfusion with G-CSF or FLT3L in a similar way as HSC and in this way, could transit from the BM into extramedullar sites expressing SDF-1. It is remarkable that injury induces in most organs, including kidney liver or brain, high levels of SDF-1 synthesis [98
99
100
], and apparent postnatal stem cell transdifferentiation has been observed only when recipients were injured shortly before stem cell injection. This suggested that postnatal stem cells of any specificity could migrate from the BM to injured tissues, most probably via SDF-1/CXCR4 interactions. Additional signals, which are expected to be tissue-specific, may be required to dock the TCSC in the injured tissue to insure its regeneration. Altogether, these observations do not argue in favor of HSC transdifferentiation upon tissue repair but rather suggest that BM suspensions contain, in addition to the HSC, a pool of TCSC, which are the very cells performing regeneration in nonhematopoietic tissues. Working with purified cell suspensions should bring the answer.
Transdifferentiation is nevertheless observed in vertebrates and is generally associated with tissue damage. For instance, the transdifferentiation of pigmented epithelial cells of the dorsal iris into clear epithelial lens cells allows the regeneration, after lentectomy, of the lens eye in newts and frogs. This process involves Hox gene (re)activation and the presence of active thrombin [101
102
103
] (for review, see ref. [104
]). Transdifferentiation can also be induced in mammalian cells, but this generally requires procedures that stand away from a natural setting. Rat MSC can differentiate into excitable neurons if they are passaged for more than 25 population doublings in vitro before incubation with mouse cerebrelar granule neurons. Cell fusion was not responsible for the process, as transdifferentiation also occurred when MSC were incubated on fixed neurons [105
]. Central corneal epithelial cells from adult rabbit can be reprogrammed to become hairs and interfolicullar epithelial cells if incubated over a murine embryonic dermis, encapsulated and grafted into a severe combined immunodeficiency mouse [106
], and human MSC, purified by adherence, differentiate into hepatocytes in vivo after direct injection into the liver of rats chronically exposed to allyl alcohol. Cell fusion was also excluded in this study, as the small proportion of the regenerating hepatocytes expressing the human y chromosome was negative for rat chromosome markers. The survival of these cells was nevertheless transient [107
]. More drastic, nuclei from terminally differentiated somatic cells, even after loss of a fraction of their DNA as a result of T cell or B cell receptor rearrangement, can be reprogrammed to reactivate zygote functions [108
, 109
]. Thus, extensive but obviously nonphysiological modifications of the environment (or the niche, which acquires an intracellular dimension in the latter case) can induce adult mammal transit stem cells or fully differentiated cells to dedifferentiate and redifferentiate into another tissue or even a new organism. These observations are in agreement with the hypothesis that stemness is a state rather than a cellular entity and can be accessible to most cells if the correct environment is provided [46
, 110
]. More specifically, these data also suggest that the stem cell niche, in addition to its self-maintaining properties, may be involved in the determination of lineage specificity. It is worth noting that most of the active genes identified during the process of cornea-to-epidermis transdifferentiation and of MSC-to-neuron transdifferentiation, i.e., Wnt/ß-catenin, Noggin/bone morphogenetic protein, and Hox genes of the Pax and the Sox family, are embryogenesis-related genes also involved in HPC/niche interactions. One cannot exclude that a postnatal stem cell, containing a great number of such genes available for transcription, may enjoy a high level of plasticity and could, after homing into an injured tissue of a different specificity, within physiological conditions, activate some of these genes to acquire the phenotype and the function of the "foreign" tissue in the same way that a transit stem cell can, in emergency situations, revert to an ancestral phenotype within its own tissue. This may indeed be absolutely required for the cell to survive and avoid differentiation. Upon injury of a peripheral tissue, one may expect that tissue-committed stem cells of various specificities are released from the BM by a local and transient decrease of SDF-1 expression in this environment. These cells will circulate until they reach the injured tissue that expresses a high level of SDF-1. Here, stem cells will target the empty niches, and these will be preferentially colonized by the tissue-specific stem cells, as cellular interactions may be more efficient between cells belonging to the same tissue. However, if tissue-specific stem cells cannot repopopulate all the niches, stem cells from another specificity may transdifferentiate via interactions involving embryonic-related genes into stem cells of the tissue of adoption. The newly transdiffentiated stem cells will then have access to all the protective interactions provided by the niche and will be rescued from uncontrolled differentiation (Fig. 2
).
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Figure 2. Hypothetical impact of stem cell niche vacancy on self-maintenance and transdifferentiation. Circles represent postnatal stem cells specific for the tissue, illustrated here with its niches forming structures appearing as "Cs". Black "Cs" represent niches for ancestral stem cells, providing all the factors sustaining self-maintenance. Shaded "Cs" are niches that lack some factors and will not fully protect stem cells from differentiation. Lightly shaded circles are ancestral stem cells, whereas darkly shaded circles are transit stem cells. Solid and open circles represent cells that have undertaken a consistent differentiation. Diamonds are circulating stem cells from another tissue. Lightly shaded diamonds are ancestral, postnatal stem cells, whereas darkly shaded diamonds are transit stem cells. In steady state, the homeostasis of the tissue could be summarized as follows (right side of figure): Stem cells feel that the number of transit stem cells in the tissue is low (i); consequently, stem cells leave their niche to escape antimitotic interactions and duplicate (ii, iii); once mitosis is completed, only one daughter cell can go back into the niche (iv); the cell that has homed back into the niche is protected from differentiation and remains quiescent, whereas the cell outside the niche is bound to proliferate and differentiate, insuring tissue homeostasis (v); in some tissues [111
], the stem cell may remain in the niche during duplication; it gets polarized and orients its mitotic spindle perpendicular to the niche so that one of the daughter cells is distal to the niche after mitosis and cannot enter it (iiib); the distal daughter cell is bound to differentiate; the lifespan of transit stem cells and functional cells is limited; however, the niches and the resting stem cells can feel the exhaustion of the transit stem cell progeny and will reiterate mitosis when needed (i). When tissue regeneration is required after ancestral stem cell destruction, three scenarios can be envisaged. (A) Autologous regeneration. Remaining transit stem cells from the injured tissue enter the vacant niches (-ii). Those transit stem cells that have reached an ancestral niche can be reprogrammed (symbolized by the boxes with an irregular shape) as an ancestral stem cell, thanks to the factors present in the niche (-i) and will be the reservoir for the tissue (i). (B) Mixed regeneration. Tissue-specific and ectopic transit stem cells are present in the injured tissue and target the empty niches (-ii). The tissue-specific transit stem cell has a higher affinity for the niches and can therefore enter the ancestral niche before the ectopic transit stem cell (-i). Both cell types are reprogrammed according to the niche characteristics and participate in tissue regeneration/homeostasis (-i). (C) Fully ectopic regeneration. Ancestral and transit stem cells of the tissue have been destroyed. Circulating ectopic stem cells home to the niches (-ii), are reprogrammed according to the niche characteristics (-i), and participate in tissue regeneration/homeostasis. This last situation would correspond to the transdifferentiation process and obviously occurs during lens regeneration in amphibians.
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Thus, transdifferentiation may be the remains of a mechanism primarily designed to spare a maximum number of postnatal stem cells, irrespective of their original specificity. That in some cases such a mechanism allows the regeneration of an injured tissue by stem cells of a different lineage certainly represents an advantage for the organism survival.
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CONCLUSION
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The intense research undertaken recently on a somatic stem cell has revealed how deeply these cells were involved in tissue homeostasis. It now seems impossible to conceive of how any tissue of the organism could survive without the presence of self-maintaining stem cells insuring tissue maintenance and regeneration in case of injury. However, despite this ever-going cell flux from the least to the most differentiated, tissues remain remarkably stable and keep assuming their function while being renewed continuously.
Postnatal stem cells are difficult to identify, as they are rather scarce within the tissues and as no consensus concerning their phenotype can be reached. No matter the tissue or the organ addressed, i.e., the liver, the medullar hematopoietic tissue, or the medullar stromal tissue, the stem cell phenotype remains evanescent, is study-dependent, and varies depending on experimental conditions.
Stem cell therapies are already used in several clinical procedures aiming at hematopoiesis, osteogenesis, skin, cornea, and liver reconstitution. Now that we have extended our knowledge as to where to harvest stem cells and how to differentiate them into various lineages, their therapeutic use will soon become more frequent. We may indeed have to respond to an increasing demand in numbers and diversity of postnatal stem cells. The most trivial approach to enlarge stem cell availability would be, as practitioners grafting solid organs do, to use cadaveric donors. However, other avenues may be at disposition. In a near future, we will certainly improve the cell culture systems and generate larger numbers of cells from small specimens. Moreover, we will continue to identify genes involved in the transdifferentiation of postnatal stem cells. Hopefully enough, this new knowledge may allow, establishing in vitro, reliable, transdifferentiation processes. This should be useful to convert postnatal stem cells from an abundant tissue into that of a tissue more limited in supply. We could imagine reverting, for clinical purposes, the experiments of Pearton et al. [106
] and transdifferentiate an upper, outer root sheath stem cell, easily available from skin, into a corneal stem cell to restore the eyesight of the patient.
All the tools required to tune up postnatal stem cells for effective therapies are here. However, aside from HSC, we miss a long-term follow-up to evaluate postnatal stem cell therapeutic efficiency and safety. Only the future will tell whether the preclinical studies initiated today will hold their promises and serve as a basis for tomorrow’s medicine.
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ACKNOWLEDGEMENTS
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This work was supported in part by the Dubois-Ferrière Dinu-Lipatti Foundation. I thank Professor Bernard Chapuis, head of the Hematology Service of the Geneva University Hospital, who continuously supported my work. He played a pivotal role in the completion of this study.
Received May 18, 2005;
accepted June 29, 2005.
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REFERENCES
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