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OPEN ACCESS ARTICLE
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TRANSLATIONAL AND CLINICAL RESEARCH: MESENCHYMAL STEM CELLS SERIES |
Laboratory for Stem Cell Research, Department of Histology and Embryology, Ankara University School of Medicine, Sihhiye, Ankara, Turkey
Key Words. Umbilical cord • Mesenchymal stem cell • Differentiation • Stroma • Wharton's jelly
Correspondence: Alp Can, M.D., Department of Histology and Embryology, Ankara University School of Medicine, Sihhiye, Ankara 06100, Turkey. Telephone: +90 533 7136967; Fax: +90 312 3106370; e-mail: alpcan{at}medicine.ankara.edu.tr
Received on June 5, 2007;
accepted for publication on July 27, 2007.
First published online in STEM CELLS EXPRESS August 9, 2007.
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ABSTRACT |
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Disclosure of potential conflicts of interest is found at the end of this article.
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INTRODUCTION |
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The UC did not gain enough attention in the 70s and 80s, most probably because of being a discarded material after delivery. Two main questions drove scientists to re-examine the Wharton's jelly stromal cells and extracellular matrix (ECM) composition in the 90s. One was the search for a possible reason and consecutive structural alterations in pre-eclampsia cases. A series of ECM components were found altered in pre-eclamptic patients associated with the "premature ageing" of this tissue [1, 2]. The second reason was the cellular identification of UC stromal cells, which basically resemble mesenchymal fibroblasts found elsewhere during in utero development. Ultrastructural studies indicated that their intrinsic properties were also similar to smooth muscle cells [3–5], and they are therefore considered myofibroblasts.
In recent years, in parallel to the enormous effort to explore novel and alternative sources of stem cells in the human body, the UC appeared as a promising reservoir of fetal cells that could be readily used as multipotent stem cells. Following the year 2003, a steep increase was noted in studies examining the stem cell potency of these myofibroblastic cells. The published articles in peer-reviewed journals written in English by July 2007 are listed in Table 1. It is very likely that many more will come in the near future, since in vivo tests of in vitro differentiated or undifferentiated UC-derived stem cells are just starting to be examined in several disease models and in regenerative medicine.
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CELLULAR AND EXTRACELLULAR MATRIX COMPONENTS OF UMBILICAL CORD |
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The inner tissue architecture is composed of a set of two arteries and one vein and a surrounding matrix of mucous connective tissue comprised of specialized fibroblast-like cells and occasional mast cells embedded in an amorphous ground substance rich in proteoglycans, mainly hyaluronic acid. Neither capillaries nor lymphatics are found in the UC. Vessels are normally organized as left spiral (counter clockwise) turns. In clinical practice, determining the "umbilical coiling index" (number of complete coils divided by the length of the cord; average 0.24 coils per centimeter) may identify the fetus at risk [12, 13].
Wharton's jelly appears to serve the function of adventitia, which the UC vessels lack, binding and encasing the umbilical vessels. It has been speculated that the stromal cells of Wharton's jelly may participate in the regulation of UC blood flow and that, at least in some cases, the reduction in fetal growth could be the consequence of stromal diminution leading to hypoplasia of umbilical vessels [14, 15]. Due to many reports and careful examination of cellular and ECM components, human UC shows a tissue compartmentalization in which cellular characteristics and ECM elements differ from each other. At least six distinctive zones are now recognized based on the structural and functional studies, from outer to inner: (a) surface epithelium (amniotic epithelium, UC epithelium), (b) subamniotic stroma, (c) clefts, (d) intervascular stroma (named classically as Wharton's jelly), (e) perivascular stroma, and (f) vessels. Fine structural, immunohistochemical [3, 4, 16, 17], and in vitro functional studies [16, 18] represented that there are significant differences in the number and nature of cells among subamniotic, intervascular, and perivascular regions, which leads to the hypothesis that those regions might be originating from different pre-existing formations. For instance, myofibroblastic cells of the intervascular stroma might have derived from adjacent vascular smooth muscle cells or, alternatively, from pre-existing fibroblasts.
Stromal Cells and Their Spatial Organization
Since structural features and main functions of UC stromal cells resemble those of fibroblasts, they were first recognized as "unusual fibroblasts" [19] and were demonstrated to be structurally responsive to the distension of cord [19]. Moderate quantities of intracytoplasmic glycogen, lipid droplets, and procollagen secretion granules, the presence of a well-developed endoplasmic reticulum with dilated cisternae, and well-developed Golgi complexes with numerous mitochondria [3, 20] directly indicated active protein synthesis and secretion. These findings, together with the demonstration of prolyl-4-hydroxylase, an enzyme involved in collagen synthesis, eventually supported the idea that UC stromal cells are primarily responsible for the synthesis of collagen and other matrix components.
The presence of an extraordinary number of 10-nm-thick intracytoplasmic filaments and gap junction type intercellular communications, as commonly observed at the interface of long cellular processes, was helpful in understanding their nature and validated their classification as "unusual" smooth muscle cells having some kind of contractile properties. Cell surfaces are partially covered by an external lamina [3–5] mainly composed of collagen type IV, laminin (Fig. 1), and heparan-sulfated proteoglycan [4]. They contain both subplasmalemmal and intracytoplasmic focal dense plaques as typically found in smooth muscle cells [17, 20], whereas no Z discs or striated-muscle filaments are observed. Membranous caveolae [4], pinocytic vesicles beneath the plasma membrane [3], and numerous dense bodies differentially located in the peripheral cytoplasm intermingled with 10-nm-thick filaments [3–5, 21] were also reported. Those studies also demonstrated the expression of some muscle-specific cytoskeletal filaments in stromal cells, a finding that supports the notion that, rather than fibroblasts or smooth muscle cells, they are true "myofibroblasts," a term that was firstly used by Majno et al. [22] to define cells that exhibit some of the ultrastructural features of both smooth muscle cells and fibroblasts. Specifically, contractile proteins such as actin, nonmuscle myosin, desmin, and 
-smooth muscle actin, a marker for myofibroblasts [23], are differentially expressed in stromal cells [3–5, 16, 21], whereas muscle-myosin is lacking [3]. Depending on the above findings, it was suggested that these cells possibly display specific functions related to both fiber synthesis and organized cell communication and contraction. Supporting evidence was the fact that those cells also express vimentin [3, 4, 16, 24], an intermediate filament protein specifically expressed in mesenchyme-derived cells, such as fibroblasts, and not expressed in smooth muscle cells [25]. The coexistence of vimentin and desmin in these cells supports the hypothesis that they are intrinsically myofibroblasts. Another interesting intermediate filament expressed by the stromal cells is cytokeratin [4, 16, 24], which is basically expressed in endoderm and ectoderm originated epithelial cells [25]. Although Nanaev et al. [4] did not find any significant expression of cytokeratins in stromal cells but in subamniotic epithelium, Karahuseyinoglu et al. [16] have demonstrated that cells of the perivascular region were strongly positive for cytokeratin filaments.
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-smooth muscle actin increases with increasing weeks of pregnancy. In fact, the density of cells in a given section differs among subamniotic, intervascular, and perivascular areas. Cell frequency is considerably low in subamniotic regions, whereas perivascular areas possess the highest cell density [3, 4, 16]. Intervascular cells possess longer and more numerous cytoplasmic processes than do perivascular cells [3]. Further analyses revealed a clearly defined spatial differentiation gradient with increasing cytoskeletal complexity in human UC stromal cells from the superficial layers toward the blood vessels [4, 5]. In parallel to this increasing differentiation status, a gradual decrease from outer to inner cells was noted in the proliferation rate of stromal cells [4]. Conclusively, the immature cells retaining the ability to proliferate are located close to the amniotic surface, whereas highly differentiated perivascular cells are found in closer proximity to the umbilical vessels.
Extracellular Matrix
Since the UC is the vital and exclusive connection providing the bidirectional blood flow between maternal and fetal sites, mechanical property of this tissue is extremely important. The consistency that prevents UC vessels from bending and occluding is mainly associated with the structure of the ECM, which has a unique tissue structure in terms of the compositions of connective tissue fibers and related soluble proteins. The first observations of the ECM in the 50s and 60s reporting the collagen skeleton in close association with the amorphous ground substance [19, 26, 27] were confirmed by later studies. The most abundant fibrillar component of the intercellular stroma as arranged in wavy thick bundles is definitely collagen fibers, whereas elastic fibers are absent [28]. Although it is a minor collagen form, the first type to be demonstrated by both immunohistochemistry and PCR was type VII collagen, found predominantly in the basal portion of the umbilical epithelium and in cultured stromal cells [29]. The extremely low solubility of collagen by chemical or organic substances [1, 30] implied that they build strong ionic bonds with glycosaminoglycans and proteoglycans, therefore providing the stroma with an extraordinary strength [30]. The spongy network of interlacing collagen fibers in a continuous soft skeleton enclosing a wide system of interconnected cavities and canaliculi-like structures, collectively defined as clefts, was thought to have a mechanical role that allowed consistency of the ground substance during twisting or compression as reported by Vizza et al. [31]. A regional distribution of collagen fibers was first noted by Nanaev et al. [4], who showed collagen types I, III, and VI in the subamniotic and intervascular regions as well as in the vessel walls. Type IV was found in both the umbilical epithelium basement membrane and external lamina of subamniotic stromal cells, whereas type VII was restricted to the epithelial basement membrane in term cord. More quantitative studies by Sobolewski et al. [30] regarding the amount of collagen showed that collagen comprised 50% of defatted, dry tissue of UC. Type I and type III collagens were found to be the most abundant forms in the intervascular region and arterial wall, that is, the amount of collagen in the stroma was reported as four times higher than in the artery wall [30]. Moreover, the ratio of type I/III was reported to be almost twice as much in arterial wall as compared with intervascular stroma [30]. Therefore, it was concluded that the resistance of collagen in the intervascular stroma to the action of collagen-solubilizing solutions may be related to the high amount of type III collagen. Another constituent of the microfibrillar network was found as typical 100-nm periodic filaments of type VI collagen [32].
A second major component of the ECM of Wharton's jelly is the ground substance, mainly composed of glycosaminoglycans (GAGs). The total amount of GAGs in Wharton's jelly is twice as high as that contained in the arteries [30]. A certain amount of GAGs is derived from the mast cells that are predominantly localized in close proximity to blood vessels [33]. Hyaluronic acid (HA), being 70% of all the GAGs, is the most abundant form; the amount of sulfated GAGs (keratin, heparan, dermatan, chondroitin-4, and chondroitin-6 sulfate) is very low, whereas heparin is found only in traceable amounts [30]. The extracellular matrix of the UC is one of the highest hyaluronic acid-containing tissues in humans [34]. However, abnormal amounts of HA in the UC are also linked to the pathogenesis of some structural defects. HA was shown to be synthesized higher than normal levels in the UCs of Down syndrome cases than in euploid UCs [34]. The mobility of HA in the intercellular stroma is reduced both by the collagen network and by the presence of proteoglycan(s) and/or microfibrils [35]. Therefore, reduction in HA mobility due to physical entanglements may play a major role in UC tissue remodeling, since a certain degree of HA mobility is vital to permeate the extracellular space.
The fibrillar component of artificially formed tissue pellets and constructs using UC stroma-derived cells showed that, under certain cultures, conditioned cells tend to accumulate and secrete a reasonable amount of collagen I and II [16, 36] when induced for chondrogenic purposes. Heparin, heparan sulfate, and aggrecan have also been found to synthesize by cultured stromal cells [36].
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ISOLATION AND CULTURE OF STROMAL CELLS |
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Cell harvesting by a tissue digestion procedure should follow a further isolation of stromal cells that would characterize stromal subpopulations depending on their specific cell surface markers. Fluorescence-activated cell sorting and magnetic immunobead separation techniques are generally used to sort and count the interested cells in a relatively short period of time. UC stromal cells have some genetic and surface markers that are also common in MSCs. Table 2 summarizes all of the cell surface markers tested so far by means of PCR, real-time PCR, microarray, and immunocytochemistry techniques. Among these, CD105, CD73, and CD90, which are known to characterize MSCs [48], were consistently found to be positive in UC stromal cells. They do not express hematopoietic stem cell markers such as CD45, CD34, and human leukocyte antigen (HLA)-DR, which are also lacking in MSCs [48]. However, some discrepancies among groups were reported. Sarugaser et al. [18] found that HLA-1 expression is only stable up to five passages and is lost after cryopreservation, whereas Weiss et al. [41] did not find any change throughout the passages. These and similar findings (Table 2) are most likely due to the epigenetic factors caused by varying culture conditions. Nonetheless, UC stromal cells are generally considered MSC-like cells, a hypothesis that is supported by many studies regarding the in vitro and in vivo differentiation potentials (see below). Stromal cells were also found to express low levels of some transcriptional factors that are mainly expressed in embryonic stem cells such as Oct-4 [41] and Nanog [46], both at the mRNA and protein levels. Additionally, these cells were found to express a low amount of Wnt-signaling pathway molecules; however, they do possess the canonical Wnt transduction mechanisms [49]. Given that these factors are among the key regulators of self-renewal and pluripotency in stem cells [50, 51], it is therefore possible to assume that UC stromal cells use similar regulatory mechanisms as embryonic stem cells, especially when dissociated from the microenvironment that can be considered their niche. Further characterization of these MSC-like cells and their niche is inevitable to fully estimate their responses due to varying differentiation recipes.
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An important issue of interest in adult stem cell studies is the availability of the source and the efficacy of isolation techniques to yield a reasonable amount of viable cells to expand. Therefore, the expansion efficiency of UC stromal cells without spontaneous differentiation is critical before they are induced to differentiate. Although the frequency of bone marrow stromal cells is often reported to range from 1–10 MSCs in a total of 106 bone marrow mononuclear cells [52, 53], the harvesting ratio of stromal cells in cord stroma is found to be relatively high (4 x 105 cells per sample, 10 x 103–5 cells per centimeter of cord) [16, 41, 42]. UC stromal cells successfully served as a feeder layer during expansion of equine embryonic stem cells derived from the inner cell mass for more than 350 divisions without any supplementation of leukemia inhibitory factor [54].
Telomerase activity (TA) in proliferating cells is an active area of research since, unlike embryonic stem cells and tumorigenic cells, somatic cells display low levels of TA [55]. Few studies dealing with the TA of human UC stromal cells revealed that TA in those cells is higher than in somatic cells of the body. Mitchell et al. [45] showed that TA in isolated porcine UC stroma cells is 10% of carcinoma cells lines, whereas Weiss et al. [41] found that telomerase reverse transcriptase gene expression is elevated in cultured human UC stromal cells. Karahuseyinoglu et al. [16] demonstrated a stable but higher than normal TA in those cells during early passages, which then decreased and reached a level below control HeLa cell lines. Since the transplanted UC stromal cells did not develop any tumorigenic formation [47], it is possible to conclude that UC-derived stem cells have a certain limit of TA that provide cells with the ability to proliferate up to 30–60 divisions but never to a level of tumorigenic state.
In view of the fact that the therapeutic use of stem cells would require freezing of cells in order to store them until thawing whenever needed, freezing conditions of isolated UC stromal cells and viability rates after thawing have to be evaluated. Most researchers prefer to use defined culture media supplemented with high amounts of fetal bovine serum and 7%–10% dimethyl sulfoxide [16, 41] or glycerol [41] and freeze the cells gradually and keep them between –135°C and –196°C [16, 18, 41]. After rapid thawing at 37°C, both viability and expansion of cells were found to be satisfactory, with viability rates over 50% [18]. The use of higher levels of fetal bovine serum especially during the first week after the thaw substantially increased growth rates [16]. Certainly, more controlled studies are needed to maximize the freeze-thaw efficiency, especially when their routine use is concerned in clinical trials.
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IN VITRO DIFFERENTIATION POTENTIAL OF UC STROMAL CELLS |
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Chondrogenic induction was investigated in a few studies using pellet cultures in conditioned media to form three-dimensional cell spheres [16, 43] or polyglycolic scaffolds [36], in which collagen fiber formation, GAG accumulation, and chondrocyte differentiation were examined. One–two-millimeter shiny-surfaced cell spheres resembling articular cartilage were formed within 3 weeks containing many chondrocytes embedded in a mucopolysaccharide-rich stroma [16]. Type II collagen was found to be most abundant [16, 36] as detected by hydroxyproline assays [36] or by immunohistochemistry [16], although type I collagen fibers were also detected, especially in the peripheral area of cell spheres, implying a capsule formation [16]. De novo synthesis of type II collagen fibers, which are normally synthesized by chondroblasts [56], indicates the functional differentiation of UC stromal cells in a cohort behavior.
Osteogenic potency was first demonstrated in 2004 by Wang et al. [43] as the formation of alkaline phosphatase-positive aggregates and von Kossa stained nodules with an associated expression of osteopontin, an osteospecific matricellular protein. Later, Karahuseyinoglu et al. [16] showed that calcium deposition and osteoid formation gradually increased up to 4 weeks, during which bone sialoprotein-2, osteonectin, and osteocalcin appeared during the 2nd, 3rd, and 4th weeks, respectively. More specifically, Sarugaser et al. [18] used perivascular cells to build mineralized bone nodules of 300–800 µm in diameter containing a collagenous ECM in their inner structure. Baksh et al. [49] showed that perivascular cells generate a greater extent of mineralization than bone marrow-derived MSCs.
Differentiation into cardiomyocytes or skeletal myocytes of UC stromal cells was less examined. Five-azacytidine, a chemical analogue of the cytosine nucleoside in the DNA and RNA helix, is currently used as a key chemical initiator of myogenic differentiation. Rat cardiac myocyte culture supernatant was added to culture media to differentiate UC stromal cells to cardiac myocytes [43]. Although cardiomyogenically induced cells synthesize -sarcomeric actinin and troponin I and T, all of which are cardiac muscle-specific proteins, and N-cadherin, a calcium dependent cell adhesion molecule [43], they did not form any sarcomeres, although Z discs between cells did form as naturally found in mature cardiac myocytes. In many studies examining the regenerative potency of transplanted MSCs, it has been directly or indirectly demonstrated that undifferentiated cells could incorporate into the myocardium and could somehow repair the injured tissue [57]. Therefore, these partly differentiated cells may hold the potency to differentiate into cardiomyocytes when appropriate in vivo signals are received. Recently, differentiation of UC stromal cells into skeletal myocytes has been successfully achieved both in vitro and in vivo (see below) [47].
Obviously, after the pioneering studies published in the late 90s and early 2000s [58, 59], differentiation of MSCs and MSC-like cells into neuronal lineages has been an interesting experimental phenomenon. Initial findings relevant to the in vitro neuron formation of porcine UC matrix cells were published in 2003 [45] in that a relatively complex and multistep neuronal induction procedure, as previously defined by Woodbury et al. [59], was used to transform the cells into a neuronal phenotype within a few days. Consequently, differentiated cells expressed tuj-1 (β-III tubulin), neurofilament (NF), neuron-specific enolase, tyrosine hydroxylase (TH), and growth-associated protein-43. Mitchell et al. [45] also demonstrated that some of the cells in the same cultures exhibited glial fibrillary acidic protein (GFAP) and CNPase positivity, indicating that a portion of cells are capable of differentiating into glial cells. Similarly, human UC cells were partially differentiated in vitro into neurons and glia in later studies [16, 41, 42, 60] in which neuronal formation was confirmed by early expressions of NeuN, NF, and GFAP and then later by the expression of functional mRNA responsible for the synthesis of subunits of the kainate receptor and glutamate decarboxylase [60]. More recently, Karahuseyinoglu et al. [16] demonstrated that only a portion of stromal cells is responsive to neuronal induction and suggested that this may be due to the presence of heterogeneous cells populations derived from the UC stroma. Supporting evidence for this came from the study of Sarugaser et al. [18], who showed that perivascular cells could not be differentiated into neurons. Recently, Baksh et al. [49] demonstrated that perivascular cells express elevated levels of CD146. Interestingly, a subpopulation of perivascular cells with no CD146 expression could not be differentiated into mesenchymal lineages.
Ma et al. [61] used a different reagent, a medicinal herb, to induce human stromal cells into neuronal lineages. Whether related or not, they found that when treated with the herb extract, human UC stromal cells were found to express pleiotrophin, a secreted growth factor that induces neurite outgrowth and is mitogenic for fibroblasts and epithelial and endothelial cells [62]. In addition to pleiotrophin, human UC stromal cells were found to secrete several neurotrophic factors, like fibroblast growth factor (FGF)-2 and brain-derived neurotrophic factor [44]. Therefore, the tendency of UC-derived stromal cells to differentiate into neuronal cells may be explained by these intrinsic properties, a hypothesis that is also consistent with the idea that these cells might function by delivery of neurotrophic agents.
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IN VIVO TRANSPLANTATION EXPERIMENTS |
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Following the above findings, engraftment of human or rat UC cells into rodents was tested to assess whether donor cells could adapt to the recipient organism and function. Two fundamental approaches were applied after isolation and expansion of cells: transplantation of cells into animal tissues in undifferentiated [41, 47] or, rarely, in differentiated forms [40]. Experimental Parkinsonian models were used to examine the recovery effects of transplanted cells in the 6-hydroxydopamine-induced brains. Weiss et al. [41] and Fu et al. [40] demonstrated that a significant decrease was noted in amphetamine-induced rotation of Parkinsonian rats by transplantation of undifferentiated UC stroma cells. Both groups also managed to induce human UC stromal cells into TH (+) dopaminergic neurons in vitro. Prior to transplantation, Fu et al. [40] induced them by a combination of sonic hedgehog protein and FGF-8 and developed TH (+), glutamate decarboxylase (+), and dopamine β-hydroxylase (+) neurons. In vitro differentiated dopaminergic cells were then transplanted into rat striatum, which had previously been damaged by 6-hydroxydopamine. Weiss et al. [41] used a similar method to transplant undifferentiated human UC stromal cells to rat striatum. Detailed work for characterization of human UC stroma cells before transplantation revealed the expression of genes related to morphogenesis, extracellular adhesion molecules, neurotrophic factors, and three germ layer derivatives. An interesting finding was that, although cells were recovered 2 days following transplantation, none were found at 6 or 12 weeks after transplantation [41]. In contrast, in a study by Fu et al. [40], transplanted TH (+) cells were detected 20 weeks after transplantation and were found to have migrated from the engraftment site. The efficacy of the stem cell treatment was determined by a decrease in the rotation behavior of transplanted animals; therefore, both groups reported a significant improvement in the behavioral recovery in a relatively long-term post-transplantation period. Although rat UC stroma was used as a stem cell source, it would be reasonable to mention the study by Jomura et al. [39], who demonstrated a decrease in neuronal loss in global cerebral ischemia when pretreated with UC stromal cells. Therefore, besides the catecholamine-synthesizing neuronal recovery attempts, studies concerning the rescue of ischemic areas in animal models also seem promising. Lund et al. [44], on the other hand, used human UC cells and human placenta-derived stromal cells to treat retinal nerve denervation in rats. Comparative results revealed a higher rescue of photoreceptor neurons obtained by UC stroma cells relative to placenta-derived cells.
In a recent study by Wu et al. [65], human UC stromal cells were differentiated into endothelial cells both in vitro and in vivo. They were induced to form endothelial cells by basic FGF and vascular endothelial growth factor and transplanted into the hind limb ischemia model of nude mice, where they differentiated into endothelial-lineage cells in vivo and subsequently became involved in the vessel network.
Cells with limited regenerative capacity, such as skeletal myocytes, are also of interest, since musculoskeletal injuries are very common. Conconi et al. [47] showed the in vitro differentiation of CD105 (+) human UC cells into skeletal myocytes, which were used to treat the bupivacaine-injured tibialis anterior muscle of rats. A striking common aspect emerging from in vivo studies is the absence of any graft rejection, which strongly gives credence to the safe use of those cells for treatment purposes, even in xenotransplantation trials.
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CONCLUSION AND FUTURE PERSPECTIVES |
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It was also shown by several experiments that UC-derived stromal cells are more efficient in terms of stem cell potency as compared with bone-marrow derived MSCs. Additionally, the shorter doubling time of cultured UC-derived stem cells compared with bone marrow MSCs [69] would give an easier and rapid propagation of these cells. Also, they do not require feeder layers or high serum concentrations to be expanded. Together with the distinct advantages of the UC, such as accessibility with little or no ethical concerns and painless procedures to donors with lower risk of viral contamination, it is generally accepted that the UC should be considered as an alternative to bone marrow. The ability to introduce exogenous DNA into the perivascular cells of UC stroma [49] makes them potent stem cells for gene therapies similar to bone marrow-derived MSCs [70]. Most recently, interferon-β expressing UC stromal cells were targeted to experimentally developed lung tumors by i.v. and subcutaneous injections and were found to significantly reduce the tumor burden [71], which indicated the usability of UC stromal cells in cancer gene therapy.
There has been a great interest in the search for novel and potent stem cell sources in the human body. As a result, a huge number of publications and meeting abstracts emerged presented by scientists, physicians, and all professionals of the relevant sectors in recent years. However, it is becoming clear that all of us need to be more cautious than ever in elucidating and interpolating our results and hopes for the future, especially for therapeutic solutions. Looking at ongoing clinical trials, it is too soon to tell whether all therapies based on stem cells will prove to be clinically effective. Nevertheless, following a sufficient number of animal experiments and clinical studies, the use of UC-derived stromal cells should be technically and ethically approved to test their ultimate potency in such diverse disease models. All we need to do as researchers in the field of UC-derived stem cells is to organize and reach a consensus on the characterization, freezing/thawing, and expansion of clinical grade cells for therapies and tissue engineering, as also suggested by Weiss and Troyer [72].
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DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST |
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ACKNOWLEDGMENTS |
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REFERENCES |
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  S. Karahuseyinoglu, C. Kocaefe, D. Balci, E. Erdemli, and A. Can Functional Structure of Adipocytes Differentiated from Human Umbilical Cord Stroma-Derived Stem Cells Stem Cells, March 1, 2008; 26(3): 682 - 691. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
