Concise Review: Recent Advances on the Significance of Stem Cells in Tissue Rege - 《stemcells》干细胞学杂志干细胞之家



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发表于 2009-3-5 00:01 |只看该作者 |倒序浏览 |打印

作者：Murielle Mimeault, Surinder K. Batra作者单位：Department of Biochemistry and Molecular Biology, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska, USA " U; i& e* N; ~, q: P9 P# I




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      【摘要】/ M+ R+ j' [! I$ C
   In this study, we report on recent advances on the functions of embryonic, fetal, and adult stem cell progenitors for tissue regeneration and cancer therapies. We describe new procedures for derivation and maturation of these stem cells into the tissue-specific cell progenitors. The localization of the adult stem cells and their niches, as well as their implication in the tissue repair after injuries and during cancer progression, are also described. The emphasis is on the interactions among certain developmental signaling factors, such as hormones, epidermal growth factor, hedgehog, Wnt/&szlig;-catenin, and Notch. These factors and their pathways are involved in the stringent regulation of the self-renewal and/or differentiation of adult stem cells. Novel strategies for the treatment of both diverse degenerating disorders, by cell replacement, and some metastatic cancer types, by molecular targeting multiple tumorigenic signaling elements in cancer progenitor cells, are also illustrated. 4 S0 k7 w$ ?* A
      【关键词】 Embryonic stem cells Adult stem cells Tissue regeneration Oncogenic transformation Stem cell-based therapies) ]. d; L( k; X  ]/ k5 `( Q1 r
   INTRODUCTION
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There is great interest in the biology of adult stem cells because of their capacity to self-renew and their high plasticity. These traits enable adult stem cells to produce diverse mature cell progenitors that actively participate in the maintenance of homeostatic processes by replenishing the cells that repopulate the tissues/organs during a lifespan and regenerate damaged tissues during injury . Parkinson and Alzheimer diseases, muscular degenerative disorders, chronic liver and heart failures, and type 1 and 2 diabetes, as well as skin, eye, kidney, and hematopoietic disorders, could be treated by the stem cell-based therapies (Table 1).
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Table 1. Therapeutic applications of embryonic, umbilical cord blood, and adult stem cell progenitors: H* y" L8 ^8 l4 P
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Genetic alterations and/or sustained activation of distinct developmental mitogenic cascades occurring in a minority of adult stem cells and their progenitors might also lead, in certain cases, to their oncogenic transformation . Molecular targeting of these oncogenic signaling elements, therefore, constitutes a promising approach for the development of novel combination therapies against these metastatic and incurable forms of cancer. In this review, we focus on the growth factor signaling cascades that might be implicated in the control of the self-renewal and differentiation of embryonic, fetal, umbilical cord, and adult stem cells and their progenitors in vitro and in vivo. Moreover, we report a description of the in vivo localization and biological functions of adult stem cells. We also describe recent advances in potential therapeutic applications of stem cell progenitors in regenerative medicine and new combination therapies for cancer treatment.
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STEM CELL TYPES! _% X, b1 r9 @% V& R% E( j
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Distinct stem cell types have been established from embryos and identified in the fetal tissues and umbilical cord blood (UCB), as well as in specific niches in many adult mammalian tissues and organs, such as bone marrow (BM), brain, skin, eyes, heart, kidneys, lungs, gastrointestinal tract, pancreas, liver, breast, ovaries, prostate, and testis . All stem cells are undifferentiated cells that exhibit unlimited self-renewal and can generate multiple cell lineages or more restricted progenitor populations that can contribute to tissue homeostasis by replenishment of cells or regeneration of tissue after injury.
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Several investigations have been carried out with isolated embryonic, fetal, and adult stem cells in a well-defined culture microenvironment to define the sequential steps and intracellular pathways that are involved in their differentiation into specific cell lineages. More particularly, different methods for in vitro culture of stem cells have been developed, including the use of cell feeder layers; cell-free conditions; extracellular matrix (ECM) molecules, such as collagen, gelatin, and laminin; and diverse growth factors and cytokines . We report here the structural and functional features of embryonic, umbilical cord, and adult stem cells and their niches, as well as the procedures that are used for their differentiation into particular cell lineages in vitro and in vivo.

Embryonic Stem Cells

Several mammalian pluripotent embryonic stem cell (ESC) lines derived from blastocyst-early-stage embryos have been established (Fig. 1) . Moreover, all ESC lines generally exhibit high levels of telomerase expression and activity for prolonged periods in culture. In this matter, ESCs possess the dual ability to undergo unlimited self-renewal and to differentiate in all fetal and adult stem cells and their more differentiated progenitors. Therefore, they represent a useful source of stem cells for investigating the molecular events that are involved in normal embryogenesis and generating a large number of specific differentiated progenitors for cellular therapies./ e( n1 r/ _5 o% e" s, S
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Figure 1. Schematic diagram showing the possible differentiation pathways of ESCs. The ESCs can give rise to three germ layers, endoderm, mesoderm, and ectoderm, during embryonic development. Similarly, ESC progenitors derived through the formation of EBs might also form teratomas corresponding to the complex structures containing the cell types from three germ layers in vivo. Moreover, the in vitro expansion and differentiation of ESC-derived progenitors in the presence of specific growth factors and cytokines in culture medium may also generate mature cell progenitors possessing the particular markers and biological features of cells constituting the tissues/organs of endodermal, mesodermal, or ectodermal origin. Abbreviations: EB, embryoid body; ESC, embryonic stem cell./ }, T2 v6 M. I9 y7 `
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In Vitro Derivation of ESC Progenitors. ESCs are generally isolated from the inner cell masses (ICMs) of blastocysts, which consist of pluripotent cell populations that are able to generate the primitive ectoderm during embryogenesis (Fig. 1). More specifically, in normal embryonic development, the primitive ectoderm gives rise during the gastrulating process to the primary germ layers, including ectoderm, mesoderm, and endoderm. These three germ layers might subsequently generate a variety of organized tissue structures involving complex epithelial-mesenchymal interactions. Similarly, the injection of ESC-derived progenitors into severe combined immunodeficient (SCID) mice might also result in the formation of teratomas corresponding to the complex structures containing the differentiated cell types from three germ layers . However, mouse and human ESCs express different marker profiles and might respond differently to certain growth factors, giving rise to distinct cell lineage progenitors. Therefore, these interspecies differences underline the importance of further establishing the particular differentiation pathways of hESC-derived progenitors for their clinical applications in humans.
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One of the critical steps in the purification procedure appears to be the enrichment of EB-derived progenitor cells by the elimination of pluripotent and undifferentiated stem cells. Indeed, the elimination of undifferentiated stem cells that may form teratomas or teratocarcinomas in vivo appears to be essential for generating transplantable sources of differentiated stem cell progenitors for the treatment of diverse disorders .

Hence, together these studies have contributed to the development of new procedures for the derivation and enrichment of hESCs. These new procedures can be used for studying the developmental pathways involved in hESCs maturation into their commitment lineages, as well as generating a variety of differentiated hESCs progenitor types for their in vitro and in vivo use. First, the development of novel purification methods to obtain a level of 100% purity of hESC-generated progenitors in the transplants seems to be necessary before they can be used in the clinic.& O7 u! G& a0 U3 I4 y! c7 U
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Embryonic and Primordial Germ Cell Carcinomas. Several works have revealed that pluripotent ESCs, as well as primordial embryonic germ cells (EGCs) that are derived from embryonic gonads, might also give rise to teratocarcinomas in vivo. As a matter of fact, the injection of adapted human ESC-derived progenitors that are obtained after prolonged culture in vitro into SCID mice might result in the formation of teratocarcinomas whose tumors are composed of cells derived from the three germ-like structures . In fact, based on the hypothesis that certain adult cancer forms might also derive from the malignant transformation of tissue-specific adult stem cells into cancer progenitor cells, the genetic alterations observed in embryonic carcinoma cells might also provide information on oncogenic gene products that might be involved in initiation of certain adult cancer types.% c% L( y" d8 |8 z6 C* V

Amniotic Epithelial Cells
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Amniotic epithelial cells (AECs) derived from the amniotic membrane in human term placenta also express the markers that are present on pluripotent ESCs and EGCs, such as Oct-4, Nanog, and alkaline phosphatase . Of therapeutic interest, AECs do not express the telomerase and form no teratomas after transplantation in vivo. Therefore, AECs constitute a source of pluripotent stem cells that might be used in transplantation for tissue regeneration.  q: j! Z( ]7 {6 H

Fetal Stem Cells2 H5 M) @. L) y' r( W1 M

Multipotent fetal stem cells (FSCs) are generally more tissue-specific than ESCs. Therefore, FSCs are able to generate a more limited number of progenitor types. One of the particular therapeutic advantages of FSCs as compared with ESCs is the fact that FSCs do not form teratomas in vivo. Moreover, the FSCs obtained up to week 12 offer the possibility of transplanting these primitive stem cells without frequent rejection reactions, in contrast to UCB and BM stem cell transplants. As a matter of fact, recent work has revealed the possibility of using FSCs or their progenitors, isolated from particular tissues, for multiple therapeutic applications involving tissue regeneration .7 N  L3 T5 y% y, A) N

On the other hand, it is interesting to note that a reciprocal fetomaternal trafficking of cells and nucleic acids has also been shown through the placental barrier during pregnancy, which might contribute to tissue repair mechanisms in different maternal organs and the growing fetus . This reflects the high plasticity and migratory potential of FSCs, which represent major advantages for their use in transplantation. More specifically, the establishment of the structural features of FSCs that enable them to cross both the placental and blood-brain barrier could allow for the improvement of therapeutic applications of neural stem cell progenitors in allowing their administration by i.v. infusion for repair of diverse brain disorders.
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Umbilical Cord Stem Cells

Umbilical cord epithelium (UCE), which appears to derive from amniotic membrane epithelium, and UCB represent other sources of multipotent stem cells that might be used for generating diverse differentiated cell types . Hence, these dendritic cells may be used as an adjuvant in immunotherapy for diverse disorders and cancers.8 Q$ r+ O0 r$ u  N  A# |% e

In addition, human UCB also contains a more primitive subpopulation of mesenchymal stem cells than adult BM, the immature cells of which express adhesion molecules, such as CD13, CD29, CD44, CD90, CD95, CD105, CD166, and major histocompatibility complex class, but not the antigens of hematopoietic differentiation, such as CD34 . Thus, it appears that the differentiation of UCB stem cells into tissue-specific adult stem cell progenitors might constitute an alternative strategy for cellular therapies of diverse disorders (Table 1).; b. q' h) N5 W! u
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Adult Stem Cells
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Numerous studies have revealed that a population of adult stem cells and supporting cells reside within specific areas designated as niches in most of adult mammalian tissues/organs, including BM, heart, kidneys, brain, skin, eyes, gastrointestinal tract, liver, pancreas, lungs, breast, ovaries, prostate, and testis (Fig. 2) .
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Figure 2. Scheme showing the tissues/organs constituting the potent targets for tissue regeneration by stem cell-based therapies. The localization of tissue-specific stem cells and their niches is shown. The tissue-specific degenerating disorders and diseases that might be treated by the transplantation of stem cell progenitors derived from embryonic stem cells, fetal stem cells, umbilical cord blood, and adult tissues/organs, including bone marrow (BM), are also indicated. The possibility of the mobilization of BM stem cells and their progenitors in the bloodstream by using the mobilizing agents is also shown. Abbreviations: bESC, bulge epithelial stem cell; CESC, corneal epithelial stem cell; CNS, central nervous system; CSC, cardiac stem cell; CXCR, CXC-chemokine receptor; eNCSC, epidermal neural crest stem cell; G-CSF, granulocyte colony-stimulating factor; HOC, hepatic oval cell; HSC, hematopoietic stem cell; KSC, keratinocyte stem cell; MPC, mesodermal progenitor cell; MSC, mechenchymal stem cell; NSC, neural stem cell; PSC, pancreatic stem cell; RSC, retinal stem cell; SDF, stromal-derived factor; SKP, skin-derived precursor.
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Figure 3. Proposed model of the cellular events associated with the tissue regeneration by adult stem cells and cancer progression originating in their malignant transformation into cancer progenitor cells. The cellular events that are implicated in the tissue regeneration after injury, including the asymmetric division of adult stem cells into transit-amplifying cells, which in turn may give rise to the mature cells that repopulate the tissue, are shown. Moreover, the malignant transformation of adult stem cells and/or their progenitors into cancer progenitor cells induced through genetic and epigenetic alterations (gene mutations, deletions, amplifications, and chromosomal rearrangements or change in DNA methylation) and whose genetic modifications might lead to the generation a heterogeneous cancer cell population is shown. The activation of numerous growth factor signaling cascades and tumorigenic signaling elements in cancer cells, which are implicated in cancer progression, as well as their molecular targeting by using the selective inhibitors for the development of novel combination therapies against the aggressive cancer forms, are also indicated. Abbreviations: COX, cyclooxygenase; CXCR, CXC-chemokine receptor; ECM, extracellular matrix; EGFR, epidermal growth factor receptor; MMP, matrix metalloproteinase; SDF, stromal-derived factor; uPA, urokinase-type plasminogen activator; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.
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Certain concepts, based on the possibility of symmetric and asymmetric divisions or populational asymmetry, have also been proposed for explaining the balance between stem cell self-renewal and differentiation , skin, and eyes) origin and the molecular events that might be implicated in their decision to undergo sustained proliferation or adopt a specific differentiation pattern under normal or pathological conditions. More particularly, the emphasis is on the adult stem cells that can give rise to a broad range of progenitors. These adult stem cells are also able to trans-differentiate in different mature cell lineages in vitro and in vivo.

Adult Stem Cells of Endodermal Origin9 W4 z: j/ T8 Z

Pulmonary Epithelial Stem Cells. The multipotent pulmonary epithelial stem cells are able to differentiate into ciliated, secretory, intermediate, and basal cells and generate the submucosal glands. Although their specific markers and niche(s) have not yet been established precisely .$ g3 f: R2 Z( `3 {* M7 P  H
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Gastrointestinal Tract Stem Cells. The replenishment of epithelial cell lineages within the gastrointestinal tract is a frequent process, occurring every 2¨C7 days under physiological conditions. This process may contribute to the generation of new cell progenitors, which repopulate the damaged tissues during diverse pathological disorders, such as inflammation and ulceration ./ w& v# p0 a. }; X) Y, L

Pancreatic Stem Cells. The mammalian adult pancreas has three tissue types: the ductal tree, the exocrine acini, which produces digestive enzymes, and the endocrine islets of Langerhans, composed of insulin-producing ß-cells, glucagon-producing -cells, somatostatin-producing -cells, and pancreatic polypeptide-producing -cells (Fig. 2). Much evidence indicates the presence of putative pancreatic stem cells (PSCs) in ductal and/or islet regions of the mammalian pancreas. The localization of the niche(s) of these putative PSCs is not yet precisely known. In this matter, the exocrine and endocrine cells appear to be produced from the differentiation of ductal cell progenitors during embryonal development . These ICCs can give rise to diverse pancreatic cell lineages, including insulin-secreting cells.
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In addition, the stem cells of other sources expressing the pancreas-developing markers, including nestin, K8, K18, neurogenin-3, and nuclear transcription factors such as IDX-1, Pax-4, Pax-6, and Isl-1, which are important for the ß-cell differentiation, might be expanded and trans-differentiated under specific culture conditions in vitro. More specifically, the differentiation of ESCs, fetal and UCB stem cells, and adult stem cells from the liver, BM, spleen, and nervous system into pancreatic insulin-producing ß-cell-like progenitors has been performed in vitro by using growth factors such as bFGF, SCF, nicotinamide, betacellulin, glucagon-like peptide, and activin A (Table 1) .
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Hepatic Oval Cells. Mature hepatocytes can undergo several cell division cycles and are responsible for continuous hepatic cell replacement during extensive liver injury. A small population of stem cells designated hepatic oval cells (HOCs) may also be involved in tissue regeneration . Thus, additional works are essential to establishing the factors that control the migration, incorporation, and homing of extrahepatic stem cells in the liver under specific in vivo conditions.! v$ _  S& z- x1 F, `5 \
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Urogenital Stem Cells$ H. r* P0 }$ v/ `. p( k% r

Mammary and Prostatic Gland Stem Cells. The regulation of the self-renewal, differentiation, and migration of urogenital stem cells and their progenitors that are localized in the mammary and prostatic glands appears to be assumed through distinct developmental signaling pathways such as hormones, EGF, hedgehog, Wnt/ß-catenin, Notch, and/or BNPs .7 H( \9 [, q5 ^( u

Similarly, a stem cell population found in the embryonic urogenital sinus epithelium from which prostatic epithelial buds develop also appears to persist in the adult prostatic epithelium and gives rise to basal and luminal epithelial cells. More specifically, a small pool of the adult prostate-specific stem cells, which show unlimited growth in a specific microenvironment and generate multiple more-differentiated epithelial cells due their striking plasticity, has recently been isolated from the proximal regions of prostatic ducts ." ^  v+ }/ j) R9 W$ J/ h! |
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Ovarian and Testicular Stem Cells. Although several lines of evidence have indicated the presence of putative multipotent stem cells, which give rise to diverse differentiated epithelial and germ cells constituting the adult mammalian ovaries and testes, their precise localization needs to be identified. As a matter of fact, the multipotent stem cells have been established from neonatal gonads, testes, and ovaries in mouse and human . These primary follicles that were formed by the oocytes and granulosa cells derived from the OSE cells could also give rise to the mature secondary oocytes in vitro. Therefore, these findings may constitute the basis for future stem cell-based research in the development of novel in vitro fertilization strategies; however, additional work is necessary to establish the functional properties of these in vitro generated human secondary oocytes before their putative use in the clinic.

Genetic modifications in testicular and ovarian somatic stem cells and germ cells in mice and humans may also lead to tumor formation. As a matter of fact, a tumor stem cell population showing stem cell-like characteristics has been established from human ovarian tumors, which proliferate and form tumors in animal models . Additional investigations are necessary to establish the specific functions of these stem cell markers, as well as other genetic alterations that may occur in adult ovary and testicular stem cells and germ cells and that may be responsible for tumor formation in humans.5 ^! S: D3 u$ i

Adult Stem Cells of Mesodermal Origin
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Bone Marrow. BM is a well-organized tissue composed of the basic elements from the stroma and hematopoietic system and located at the center of large bones (Fig. 2). BM contains HSCs and stromal stem cells that collaborate in a reciprocal manner at all stages, leading to the generation of different BM and bloodstream cell lineages .
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Hematopoietic Stem Cells. In the adult BM, the HSCs are localized near endosteal bone surface and sinusoidal endothelium, suggesting that these sites could constitute the principal niches for their homing in BM under physiological conditions and for engraftment of HSCs after systemic transplantation (Fig. 1) . Further investigation is necessary to establish the specific signals that govern the rate of proliferation, differentiation, and migration of HSCs under physiological and pathological conditions. This should allow us to identify the specific functions that are associated with each type of HSC that is localized in BM and other distant sites, such as spleen and liver.
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In addition, HSCs and their progenitors may also be obtained from different sources, including ESCs, FSCs, and UCB as well as adult BM and MPB, and differentiate in vitro and ex vitro into different hematopoietic cell lineages .# z3 L) o0 m" }
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Stromal Stem Cells. The BM stroma is a highly vascularized, complex structure containing mesenchymal stem cells and extracellular matrix elements supporting for hematopoiesis .! V# E8 x* }7 y# Z; k" ]& F  i
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It has been reported that the stromal stem cells from BM may be involved in continuous bone remodeling, as well as in the regeneration of injured bone, cartilage, and other distant tissues, such as the liver, lungs, gut, and heart, in adults .& j- H5 _' j/ W( U6 k
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Cardiac Stem Cells. The clusters of multipotent cardiac stem cells (CSCs) expressing the cell surface antigen Sca-1, KIT, and/or multidrug resistance transporter gene 1 (MDR1) in variable combinations have recently been identified and localized throughout the myocardium, and more particularly, at the atria and lower region of the left ventricle of the heart, termed apex (Fig. 2) . Thus, it appears that the multipotent quiescent CSCs and neural crest stem cells that reside in the adult mammalian heart may contribute to the regeneration of different cardiac cell lineages following injury.% C+ T0 ~% G0 y3 Z4 f

Stem Cells of Ectodermal Origin+ n5 k, T6 c+ }0 l( H8 `5 w8 ~
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Neural Stem Cells. During prenatal development of the mammalian CNS, the neural stem cells (NSCs) and their progenitors may expand and give rise to the functional neurons and glial cells that constitute the growing brain . Hence, the generation of new differentiated neural cells from adult neural stem cells in the specific brain regions during a lifespan might assume the maintenance of CNS homeostasis and functions, particularly for learning and memory.. U. e* t/ R" G, O! w9 y+ F
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In Vivo Proliferation and Differentiation of NSCs. Several studies have been undertaken to establish the microenvironmental and intrinsic factors that might influence the behaviors of adult NSCs in vivo. Among the numerous growth factors and adhesion molecules that may be involved in the regulation of proliferation, maturation, and/or migration of adult NSCs, there are EGF, bFGF, SHH, Wnt/ß-catenin, Notch 1 ligand jagged 1, platelet-derived growth factors (PDGFs), ciliary neutrophic factor, VEGF, thyroid hormone T3, dopamine, NGF, neuregulins, BMPs, TGF-ß, Ephrins/Ephs, leukemia inhibitory factor (LIF), and integrins . This suggests that the endogenous VEGF from endothelial cells might also contribute of paracrine fashion to the NSC activation in vivo. Based on the knowledge of the factors involved in the regulation of embryonic and adult NSC growth, survival and differentiation in vivo, several new methods for in vitro expansion and differentiation of embryonic and adult NSCs have been conceived.

In Vitro Expansion and Differentiation of NSCs. Results from numerous studies have revealed that the human and rodent NSC progenitors derived from ESCs, UCB, fetal brain, MSCs, or skin-derived stem cells or isolated from adult brain tissues might be expanded in vitro or ex vivo in floating clusters called neurospheres in the presence of exogenous EGF, bFGF, SHH, and/or LIF. Moreover, the withdrawal of these mitogens and the addition of serum, RA, BNP, TGF-ß type III, and/or ascorbic acid may promote their differentiation in the three major neuronal cell types, including neurons, astrocytes, and oligodendrocytes (Table 1) . Hence, together these works have identified certain growth factors and cytokines that might promote the expansion and differentiation of embryonic, fetal and adult NSCs into the specific neuronal cell lineages and possibly constitute the basis for the development of novel therapies for a variety of CNS disorders.: C( f; r8 G+ o# y4 z0 }9 w
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Skin Stem Cells. In adult mammalian skin, the epithelial compartment consists of the interfollicular epidermis (IFE) and its related appendages, such as the hair follicles and sebaceous glands. Numerous studies have revealed that the upper region of hair follicles, the bulge area, constitutes the principal niche of multipotent stem cells, which are responsible for the long-term growth of the hair follicles and epidermis regeneration after injury (Fig. 2) .- f& y: {* m9 n/ n1 f, a9 p4 c

The bulge area in adult mammalian hair follicle also contains a pluripotent epidermal neural crest stem cell (eNCSC) population that shows several properties similar to embryonic neural crest stem cells (Fig. 2) .

In addition, the keratinocytes constituting the basal layer of epidermis also need to undergo a continuous expansion to replenish the terminally differentiated epithelial cells in the corneous layer of normal epidermis, which are shipped out of skin during the desquamation process . In this matter, since bESCs might also give rise to cells constituting IFE after injury, additional investigations appear necessary to determine the specific implication of bulge stem cells versus KSCs residing near the basement membrane during the different stages leading to the epidermis regeneration after trauma and carcinogenesis.  X: p7 h! ^7 z  i/ K

Ocular Stem Cells. The human ocular surface epithelium includes the corneal, limbal, and conjunctival stratified epithelia. Several recent lines of evidence have revealed that the corneal epithelial stem cells (CESCs) are localized at the basal cell layer of the peripheral cornea, and particularly at the limbus within the limbal epithelial crypts (Fig. 2) . These stem cell-derived TA cells could also migrate at the endothelial periphery, suggesting their possible implication in eye endothelium regeneration.% f0 o7 N6 T; }- n( \; P* y

A small population of mitotic quiescent neural stem cells has also been identified in the ciliary epithelium (CE) region adjacent to the retina in adult mammalian eyes, which may proliferate in response to retinal injury in vivo or after treatment with specific exogenous growth factors in vitro (Fig. 2) . Hence, the discovery in the adult eyes of limbal CESCs and RSCs in CE, which possess immature epithelial and neural cell properties, respectively, offers the possibility to use these stem cell types for the repair of corneal epithelium and retinal damages.

STEM CELL-BASED THERAPIES$ n  y. k: t4 w: G' `" O
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The possibility of using stem cells and their more differentiated progenitors to treat numerous degenerative disorders has stimulated great interest in developing safe transplantable sources of stem cells that are unable to form the teratomas but able to repopulate damaged tissues. Many recent investigations have provided interesting clinical findings about the possibility of using the progenitors derived from ESCs, AECs, FSCs, and UCB and BM stem cells, as well as other adult tissue-specific stem cells in genetic and cellular therapies for a wide variety of pathological processes, including degenerative, autoimmune, and genetic diseases. Clinical transplantation procedures for stem cells, which depend on patient state and diagnosis, generally involve the i.v. injection or subcutaneous administration of a specific number of stem cells directly into therapeutically targeted areas (Fig. 2). Among the disorders that might benefit from stem cell-based therapy are diabetes, acute liver and heart failures, muscular disorders, arthritis, brain damages and disorders, vision disorders, renal disorders, and hematopoietic and immune diseases, as well as acute leukemia and lymphoma and diverse solid tumor types . In addition, molecular targeting of tumorigenic cascade elements in tissue-specific cancer progenitor cells, which are derived from the malignant transformation of adult stem cells, also represents a novel approach for the treatment of diverse metastatic and incurable cancer types by combination therapies. We report the recent advances on the more promising stem cell-based strategies that have been developed in past years for the treatment of numerous degenerative disorders and aggressive cancer types./ l+ G  C9 z; b
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Regenerative Medicine

Pancreatic Diseases. Numerous studies have been undertaken to establish the insulin-producing ß-cell-like progenitors for the development of new treatments of type 1 and 2 diabetes mellitus. In fact, the replacement of insulin-producing pancreatic islet ß-cells that are destroyed or reduced in number results in the insulin deficiency and fasting hyperglycemia and constitutes a promising strategy. The ß-cell-like progenitors derived from human and mouse ESCs, fetal and UCB stem cells, and adult stem cells from pancreas and BM, showing the capacity to secrete insulin, have been obtained in vitro . This observation then suggests that HOCs could also constitute another source of pancreatic cells for the treatment of diabetes. Thus, it now appears possible to conceive the development of cell replacement therapies for human diabetic patients by using human stem cell-derived ß-cells. Nevertheless, additional work on the identification of specific factors that are involved in the migration and trans-differentiation of BM and liver stem cells into insulin-producing islet ß-cell-like progenitors in vivo is needed. In addition, the functional properties of ex vivo and in vitro expanded ß-cells in distinct animal models in vivo are essential. Optimization of these protocols is essential before their translation into clinical applications for humans. In this matter, the establishment of in vitro methods for obtaining a large amount of functional ß-cells and the optimization of delivery site are also important factors that must be considered for improving their therapeutic efficacy in the long-time treatment of patients.

Cardiac Diseases. The generation of new myocytes from endogenous multipotent CSC pools offers the possibility for maintaining cardiac homeostasis and tissue regeneration after heart hypertrophies and failures. The stimulation of the proliferation, survival, and/or differentiation of the endogenous CSCs and their progenitors may be performed by using the specific growth factors that are involved in the control of cardiogenesis and neo-angiogenesis, such as VEGF, HGF, IGF-1, EPO, TGF-ß, HIF-1, and IL-8 . Despite this advance, the lack of knowledge of the molecular mechanisms that are responsible for human CSC (hCSC) senescence, as well as the difficulties associated with the procedures of the isolation and in vitro expansion of functional hCSCs, limit their clinical applications as effective therapies for myocardial regeneration.6 q: \+ q; {- U; P4 ~( V* J& `* S
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In addition, another alternative may consist of the expansion and trans-differentiation of other stem cell types into cardiac cell progenitors in vitro or in vivo under specific conditions that may also enable them to engraft and regenerate the functional cardiomyocytes and endothelial cells for the reconstitution of damaged myocardium after injury. More particularly, several recent investigations indicated that the transplantation of ESC- and BM stem cell-derived cardiac cell progenitors might result in stable and functional intracardiac grafts in human and rodent, thereby improving cardiac functions by regenerating the infarcted myocardium . Hence, it appears that the ESC- and BM stem cell-derived cardiac cell progenitors could constitute a more accessible source of stem cells than CSCs for the treatment of diverse cardiac disorders. Additional long-term trials on large populations in human are necessary to establish the functional properties of these cardiac progenitors and their efficacy for the recovery of cardiac function after transplantation.
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CNS Disorders and Diseases. The stimulation of adult neurogenesis in vivo by supplying specific growth factors and cytokines, such as G-CSF and SCF, that stimulate intrinsic NSC progenitors and BM-derived neuronal cells or delivery of exogenous NSC progenitors constitute the novel strategies that are very promising for restoring the impaired functions in numerous damaged brain areas after ischemia, seizures, and traumas or in diverse degenerative disorders (Table 1; Fig. 2) .
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Parkinson and Alzheimer Diseases. The motor dysfunctions that are associated with Parkinson disease result from the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, a region of brain that controls muscle movement. Therefore, cell replacement therapy by delivering new dopaminergic neurons represents a putative strategy for the treatment of this neurodegenerative disease .

Spinal Cord Injuries. Since the major cause of neurological disability in spinal cord injuries is oligodendrocyte death leading to demyelization and axonal degeneration, rescuing the oligodendrocytes and preserving myelin should result in a significant improvement in the functional outcome after such injuries. It has been reported that the addition of oligodendrogenic factors such as SHH, bFGF, and PDGF might result in the differentiation of NSCs into oligodendrocyte progenitor cells (OPCs) in vitro. However, the rate of OPC differentiation of NSCs under these conditions was only approximately 10%. Interestingly, the transient expression of oligodendrogenic helix-loop-helix transcription factor Oligo 2 in NSCs, which is essential for oligodendrocyte lineage specification, may induce a high rate (approximately 55%) of OPC differentiation and generate the mature and functional oligodendrocytes expressing the transcription factor Nkx2.2 and all major myelin-specific proteins . Thus, on the basis of these observations, it now appears possible to conceive novel stem cell-based therapies for a variety of brain disorders. At this time, there exist only palliative treatments for these diseases. In this matter, the development of new strategies for the delivery of NSCs and their progenitors in the specific brain damaged areas or selective activation of endogenous NSC-derived progenitor subset should also contribute to improving their potential therapeutic applications in humans.
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Ocular Disorders and Diseases. CESCs and RSCs, isolated from the limbal epithelium and CE of adult eyes, respectively, are able to incorporate and reconstitute the damaged tissues in vivo. Therefore, they may be transplanted for the repair and regeneration of ocular surface damages. Several types of treatment for ocular disorders have been developed based on the use of limbal CESC transplants and bioengineered ocular surface tissue-equivalents for the replacement of ocular damaged tissues . Further investigation of the behaviors of endogenous CESCs and RSCs and their progenitors in eyes should allow us to conceive new methods for the functional recovery of partial ocular defects by their stimulation by diverse exogenous growth factors. Additional in vivo trials on the functional properties of ex vivo and in vivo expanded CESCs and RSCs, as well as the precise functions of amniotic membrane, are also necessary to establish the molecular mechanisms that are responsible for their therapeutic effects. These studies should contribute to improving the long-term survival rate of these adult stem cells after engraftment and thereby to their beneficial effects for the treatment of eye diseases.

Blood and Immune System Disorders. HSCs and their progenitors, which might be obtained from different sources including UCB, fetus, BM, and MPB, represent potent cells for autologous or allogeneic transplantation in the patients with hematological and autoimmune diseases .
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Table 2. Deregulated gene products in cancer cells and their molecular targeting as anticarcinogenic therapies
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Cancer Therapies
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Numerous studies have indicated that several human cancer types, including those of the blood, brain, skin, lung, kidneys, gastrointestinal tract, pancreas, liver, ovarian, prostate, and testis, might arise from the malignant transformation of stem cells and their progenitors into cancer progenitor cells . In fact, it has been observed that only these malignant cells were able to give rise to a heterogeneous population of more differentiated cancer cells in vitro and to reconstitute the original cancer-like tumors in NOD mice in vivo. Thus, on the basis of these observations, it appears that the elimination of this minority of cancer progenitor cells with stem cell-like properties, which are responsible for tumor formation, is essential for the development of more effective curative treatments against these aggressive cancer types.
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Several in vitro and in vivo studies have been carried out with a variety of cancer cell line types and on different animal models to identify new therapeutic targets to block the growth and/or survival of the cancer cells. Among them, the molecular targeting of distinct oncogenic signaling elements, which are activated in the cancer cells during the progression of numerous cancer, represents a promising strategy for the development of new chemopreventive treatments and combination therapies against some aggressive and metastatic cancers (Table 2; Figs. 3, 4). The aberrant expression and/or activity of diverse hormones, growth factors, cytokines and chemokines (androgens, estrogens, EGF and TGF-/EGFR, IGF/IGFR, SHH/SMO, Wnt/ß-catenin, Notch, TGF-ß, and SDF-1/CXCR4), and tumorigenic signaling elements (telomerase, phosphatidylinositol 3-kinase . Therefore, their molecular targeting is of importance to the elimination of cancer progenitor cells, thereby inducing a complete tumor regression and cancer remission. We report here a brief description of new therapeutic drugs that are able to block the specific growth factor signaling cascades that are frequently deregulated in the stem cell-derived cancer progenitor cells, as well as the advantages that are associated with the use of high-dose chemotherapy (HDCT) with hematopoietic cell support.

Growth Factor Signaling Inhibitors
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EGFR Family Member Inhibitors. Numerous preclinical and clinical trials have indicated that the selective blockade of the EGFR family member signaling, and particularly EGFR (ErbB1) or erbB2 (Her2), might represent a potent strategy, alone or in combination with other conventional treatments for numerous aggressive cancer forms . The inhibition of EGFR was also accompanied by cancer cell growth inhibition.
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Figure 4. Proposed strategies for the development of novel combination therapies by targeting distinct oncogenic signaling pathways in cancer cells. The possible mitogenic and anti-apoptotic cascades induced through EGFR, hedgehog, Notch, and Wnt/ß-catenin signaling pathways, which can be involved in the stimulation of sustained growth, survival, and/or migration of cancer cells, are shown. Moreover, the possible growth inhibitory and/or apoptotic effects induced by the selective inhibitors of EGF-EGFR system (gefitinib), Smoothened hedgehog signaling element (cyclopamine), Notch signaling (-secretase inhibitor), and Wnt cascade by using anti-Wnt antibody on the cancer cells are also indicated. Abbreviations: APC, adenomatous polyposis coli; CDK, cyclin-dependent kinase; CoA, coactivators; Cyt c, cytochrome c; Dsh, Dishevelled; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; Fzd, Frizzled receptor; GSK, glycogen synthase kinase; ICN, intracellular domain of Notch; LEF, lymphocyte enhancer factor; LPR, lipoprotein coreceptor; MAPK, mitogen-activated protein kinase; MEK, extracellular signal-related kinase kinase; NF-B, nuclear factor-B; PI3K, phosphatidylinositol 3-kinase; PLC, phospholipase C; PTCH, Sonic hedgehog-patched receptor; SHH, Sonic hedgehog; SMO, Smoothened; TCL, T-cell factor.& @1 m8 Q% J/ z+ R+ A
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Hedgehog, Wnt/ß-Catenin, and Notch Signaling Inhibitors. The inactivating mutations in the hedgehog receptor patched (PTCH) and/or activating mutations in the hedgehog signaling element, SMO, might increase the incidence of BCC, medulloblastoma, and rhabdomyosarcoma .: q1 V% W0 P, ]3 X! z, Q1 Y
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In addition, molecular targeting of the canonical Wnt/ß-catenin signaling elements (which may contribute to the malignant transformation of cancer progenitor cells and the progression of numerous cancers, including upper gastrointestinal tract, colorectal, pancreatic, mammary, prostatic, and epidermal cancers, as well as non-small-cell lung carcinoma, hepatoblastoma, medulloblastomas, and multiple myeloma) constitutes another anticarcinogenic strategy for the treatment of these cancer forms .& o+ n  Z% r' s( L0 F$ ~1 g; ?

Combination Therapies. The simultaneous inhibition of diverse hormone and growth factor signaling pathways, including ER, AR, IGFR, EGFR, hedgehog, Wnt/ß-catenin, Notch, and/or G-protein-coupled receptors, as well as VEGFR and PDGFR cascades, which can act in cooperation by stimulating the growth, invasion, and metastatic spread of cancer cells at distant sites during the different stages of cancer progression, may also constitute more effective therapies against the aggressive and highly metastatic cancer forms .  f1 R3 G- Q+ K1 [/ f. U9 U

Since the metastatic spread of diverse tumor cells, including those from glioblastomas, melanomas, and pancreas, breast, and prostate cancers to other specific tissues/organs, such as lymph nodes, bone, lungs, and/or liver, appears to be governed by the expression of diverse angiogenic factors, such as VEGF-VEGFR system, matrix metalloproteinases, urokinase-type plasminogen activator (uPA), cyclooxygenase-2 (COX-2), chemokines, and surface adhesion molecules, their molecular targeting may also constitute another adjuvant cancer therapy (Table 2; Fig. 3) . Altogether, these recent studies have indicated that molecular targeting of EGFR signaling, alone or in combination with other cytotoxic agents, may constitute a putative strategy for conceiving more effective clinical treatments against a variety of aggressive cancers.6 C4 H+ }; \, l- @( ^9 K1 T

High-Dose Cancer Therapy Plus HSCs. Stem cell transplantation may also constitute an option as adjuvant therapy for cancer, particularly in the patients receiving high doses of chemotherapeutic agents and/or radiation that, along with killing cancer cells, cause the severe damage to normal tissues and/or destroy the hematopoietic cells. Thus, the stem cell transplants might replace the endogenous stem cells destroyed by high-dose cancer treatment, thereby producing healthy hematopoietic cell lineages and improving the immune system defense. The autologous or allogeneic transplantation of UCB, BM, or MPB stem cells and their progenitors might be effectuated in combination with HDCT for numerous aggressive cancer forms to replace BM and blood-forming cells that have been destroyed by chemotherapy. AML and high-grade lymphoma are among the principal types of cancer that are usually treated with hematopoietic cell support as adjuvant therapy .
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In addition, transplantation or mobilization of HSCs and their progenitors in systemic circulation is often used as immune support in combination with HDCT for the treatment of patients with certain highly aggressive solid tumors, and more particularly in advanced and metastatic stages of germinal cell tumors, retinoblastoma, myeloma, brain, lung, kidney, breast, and ovarian cancers .

CONCLUSIONS6 a4 m0 v* I! `6 w# n

These recent works in the field of stem cell biology have identified intrinsic mitogenic signaling cascades that are activated in mammalian embryonic, fetal, and adult stem cells during the normal process of self-renewal and differentiation. These cellular events may also be implicated in the regenerating process after tissue injuries. Hence, this offers the possibility of differentiating these stem cell types into the specific mature cell lineages in vitro, ex vivo, and in vivo by using appropriate growth factors and cytokines for their use in basic research, as well as in transplantation for diverse degenerative disorders. Several molecular targeting therapies may also be conceived by blocking distinct developmental signaling cascade elements, such as EGFR, hedgehog, Wnt/ß-catenin, and/or Notch pathways, which are frequently upregulated in cancer progenitor cells during the initiation and development of a variety of aggressive and metastatic cancers.4 N# q4 _6 v% W- l8 L4 H

PERSPECTIVES AND FUTURE DIRECTIONS
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Further in vitro and in vivo investigations with the human embryonic, fetal, UCB, and adult stem cells and their more differentiated progenitors in different systems, animal models, and humans appear to be essential to determine their functional properties during long time periods. Detailed analyses of structural and biological properties of differentiated progenitors established from human stem cells in vitro in comparison with those of endogenous adult stem cells are highly needed before they are used in the clinic. In this direction, additional studies on human adult stem cell biology appear to be particularly essential because of the interspecies differences that may influence their capacity to give rise to the specific cell lineages under well-defined conditions in vitro and regenerate a particular tissue in vivo. In addition, the optimization of purification and delivery methods of stem cells and their progenitors appear generally to be important before their possible use under safe conditions in cellular therapies. More specifically, the establishment of the procedures of derivation from EB-derived progenitor cells in culture for the elimination of residual pluripotent and undifferentiated hESCs, which are able to form the teratomas or teratocarcinomas in vivo, is necessary before they are used in transplantation for diverse degenerative disorders in humans. In addition, further work is important to identify the specific biomarkers of adult stem cells and their progenitors, as well as the microenvironmental factors that might induce their self-renewal, maturation, and migration during each stage, leading to tissue regeneration, and during their relocation to other distant damaged tissues. These future studies should elucidate the sequential cellular events that are implicated in the maintenance of tissue homeostasis, thereby establishing the deregulated signaling that may contribute to diverse disorders and cancer types. Furthermore, since certain lines of evidence have also indicated that certain adult stem cells might trans-differentiate into mature and specialized cells from other tissue types under specific culture conditions in vitro and after transplantation in vivo, it will be important to establish more precisely the factors influencing their incorporation in healthy and damaged tissues/organs in vivo.

Several similarities appear to exist between the behavior of adult stem cells and the cancer progenitor cells, including their high capacity to self-renew and give rise to a heterogeneous population of more differentiated cells and their high capacity to migrate at distant sites, where they may establish their novel homing through interactions with their new microenvironment. Therefore, the knowledge that will be acquired on the adult stem cell biology under physiological and pathological conditions should aid particularly in the design of new cancer therapies targeting cancer progenitor cells. In this matter, it will be important to establish the specific oncogenic alterations occurring in cancer progenitor cells versus their more differentiated progenitors within the global tumor cell population during localized tumor development and dissemination to other distant tissues. Additional analyses of possible interactions between diverse developmental signaling (such as hormones, EGFR, hedgehog, Wnt/ß-catenin, and Notch pathways that are involved in the regeneration of numerous tissues and frequently activated during the malignant transformation of adult stem cells into cancer progenitor cells) are notably of particular interest. The possibility that the pharmacological agents acting on the cancer progenitor cells may also alter the behaviors of normal stem cells also emphasizes the importance of using these types of agents at lower doses in combination with conventional cancer treatments.
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Altogether, these future works should establish molecular changes occurring in adult stem cells and their progenitors during tissue repair and etiopathogenesis. Hence, these further studies could lead to the development of more effective treatments for numerous genetic and degenerative disorders by cell replacement. Moreover, the identification of specific markers and targeting distinct tumorigenic cascades in cancer progenitor cells should also contribute to developing novel early detection methods and combination therapies for diverse aggressive and lethal cancers derived from the malignant transformation of adult stem cells.
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DISCLOSURES9 s( m' C: ^8 F' n6 |( F
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The authors indicate no potential conflicts of interest.1 M* B. {. l( o% v
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ACKNOWLEDGMENTS

This work was supported by U.S. Department of Defense Grants PC040493, PC04502, and OC04110 and NIH Grants CA78590, CA72712, and CA111294. We thank Kristi L. Berger for editing the manuscript.
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