NOTE: An enormous literature is rapidly developing on the topic of adult stem cells and their potential for developmental plasticity and regenerative medicine. This bibliography lists recent comprehensive reviews and some representative articles.

1. .The significant cardiomyogenic potential of human umbilical cord blood-derived mesenchymal stem cells in vitro. Nishiyama N, Miyoshi S, Hida N, Uyama T, Okamoto K, Ikegami Y, Miyado K, Segawa K, Terai M, Sakamoto M, Ogawa S, Umezawa A. Stem Cells. 2007;25:2017-2024.

Umbilical cord blood-derived mesenchymal stem cells (UCBMSCs) are potentially a new cell source for stem cell-based therapy. In this study, human UCBMSCs (5 x 10(3) per cm(2)) were cocultured with fetal murine cardiomyocytes ([CM] 1 x 10(5) per cm(2)). On day 5 of cocultivation, approximately half of the green fluorescent protein (GFP)-labeled UCBMSCs contracted rhythmically and synchronously, suggesting the presence of electrical communication between the UCBMSCs. The fractional shortening of the contracted UCBMSCs was 6.5% +/- 0.7% (n = 20). The UCBMSC-derived cardiomyocytes stained positive for cardiac troponin-I (clear striation +) and connexin 43 (diffuse dot-like staining at the margin of the cell) by the immunocytochemical method. Cardiac troponin-I positive cardiomyocytes accounted for 45% +/- 3% of GFP-labeled UCBMSCs. The cardiomyocyte-specific long action potential duration (186 +/- 12 milliseconds) was recorded with a glass microelectrode from the GFP-labeled UCBMSCs. Cardiomyocytes (CM) were observed in UCBMSCs, which were cocultivated in the same dish with mouse cardiomyocytes separated by a collagen membrane. Cell fusion, therefore, was not a major cause of CM in the UCBMSCs. Approximately half of the human UCBMSCs were successfully transdifferentiated into cardiomyocytes in vitro.

The authors conclude that UCBMSCs can be a promising cellular source for cardiac stem cell-based therapy.

2. Neuronal conditioning medium and nerve growth factor induce neuronal differentiation of collagen-adherent progenitors derived from human umbilical cord blood. Arien-Zakay H, Nagler A, Galski H, Lazarovici P. J Mol Neurosci. 2007;32:179-91.

Research in the field of neuronal progenitors is rapidly advancing, driven by the potential use of these cells for cellular therapy of neurodegenerative disorders, stroke, trauma and spinal cord injuries. Since the availability of human neuronal stem cells derived from early embryos is extremely limited, progenitors of other origins are being considered. Human umbilical cord blood (HUCB), has served as an alternative source of hematopoietic stem cells. The biological properties of HUCB attest to the existence of progenitors of multi-lineage capacity, similar to those of BM-derived mesenchymal stem cells. Exposure of these HUCB progenitors to non-selective differentiating agents, such as retinoic acid, DMSO, and betamercaptoethanol, induce properties typical of neuroectodermal-derived cells. The HUCB-derived progenitors may prove useful in a variety of cell-based therapies, including neurological disorders.

The aim of the study was to isolate and characterize a population of neuronal progenitors in HUCB mononuclear cell (MNC) fraction, for in vitro manipulation towards neuronal differentiation. Selection of the HUCB neuronal progenitors (HUCBNPs) was based on the neuronal prerequisite for adherence to collagen. Populations of collagen-adherent, nestin-positive (94.8+/-2.9%) progenitors expressing alpha1/2 integrin receptors, as revealed by Western blot and adhesion assay using selective antagonists, were isolated and survived for more than 14 days. In vitro differentiation of the HUCBNPs was achieved by treatment with 10% human SH-SY5Y neuroblastoma cell-conditioning media (CM) supplemented with 10 ng/ml nerve growth factor (NGF). Some 83+/-8.2% of the surviving progenitors acquired a neuronal-like morphology, expressed by cellular outgrowths of different lengths. About 35+/-6% of the HUCBNPs had long outgrowths with a length/cell diameter ratio greater than 2, typical of developing neurons.

The majority of these progenitors, analyzed by immunocytochemistry and/or RT-PCR, expressed common neuronal markers such as microtubule-associated protein 2 (MAP-2; 98.5+/-2%), neurotrophin receptor (TrkA; 98.5+/-0.06%), neurofillament-160 (NF-160; 94.2+/-1%), beta-tubulin III (89.8+/-4.2%) and neuron specific enolase (NSE). Combined CM and NGF treatment induced constitutive activation of the mitogen-activated protein kinases ERK2 (36-fold vs control), p38alpha (nine-fold vs control) and p38beta (23-fold vs control), most likely related to survival and/or differentiation.

The results point to operationally defined conditions for activating neuronal differentiation of HUCBNPs ex vivo and emphasize the crucial role of neuronal CM and NGF in this process.

3. Identification of functional endothelial progenitor cells suitable for the treatment of ischemic tissue using human umbilical cord blood. Nagano M, Yamashita T, Hamada H, Ohneda K, Kimura K, Nakagawa T, Shibuya M, Yoshikawa H, Ohneda O. Blood. 2007;110:151-160.

Neovascularization in adults is recognized in the process of angiogenesis involving the recruitment of pre-existing endothelial cells in ischemic tissues. Recent studies suggest that BM-derived endothelial progenitor cells (EPCs) also play an essential role in the process of vasculogenesis. EPCs derived from PB, UCB and BM have been shown to be involved in neovascularization during vascular injury, ischemia and tumor growth. So far, the clinical applications for EPC transfusion are limited because of the small number of available cells. UCB has an advantage over PB and BM as a source of EPCs because of its accessibility and higher EPC content.

Umbilical cord blood (UCB) has been used as a potential source of various kinds of stem cells, including hematopoietic stem cells, mesenchymal stem cells, and endothelial progenitor cells (EPCs), for a variety of cell therapies. Recently, EPCs were introduced for restoring vascularization in ischemic tissues. An appropriate procedure for isolating EPCs from UCB is a key issue for improving therapeutic efficacy and eliminating the unexpected expansion of nonessential cells.

The authors report a novel method for isolating EPCs from UCB by a combination of negative immunoselection and cell culture techniques. In addition, EPCs were divided into 2 subpopulations according to the aldehyde dehydrogenase (ALDH) activity. EPCs with low ALDH activity (Alde-Low) possess a greater ability to proliferate and migrate compared to those with high ALDH activity (Alde-High). Moreover, hypoxia-inducible factor proteins are up-regulated and VEGF, CXCR4, and GLUT-1 mRNAs are increased in Alde-Low EPCs under hypoxic conditions, while the response was not significant in Alde-High EPCs. In fact, the introduction of Alde-Low EPCs significantly reduced tissue damage in ischemia in a mouse flap model. Thus, the introduction of Alde-Low EPCs may be a potential strategy for inducing rapid neovascularization and subsequent regeneration of ischemic tissues.

4. Therapeutic potential of human umbilical cord-derived stem cells in ischemic diseases. Wu KH, Zhou B, Mo XM, Cui B, Yu CT, Lu SH, Han ZC, Liu YL. Transplant Proc. 2007;39:1620-1622.

The aim of this study was to investigate the therapeutic potential of human umbilical cord-derived stem (UCDS) cells in ischemic diseases. The UCDS cells were characterized by flow cytometry and differentiation into osteogenic and adipogenic cells. Unilateral hind limb ischemia was surgically induced by femoral artery ligation in nude mice. The animals were intramuscularly injected with 10(6) UCDS cells or control phosphate-buffered saline. Blood perfusion of ischemic limbs was detected by laser Doppler perfusion imaging. Transplantation of UCDS cells to the ischemic limbs of nude mice significantly improved the blood flow to the affected limbs. Thus, transplantation of UCDS cells may potentially be a promising treatment for human ischemic diseases.

5. Identification of stem cells from human umbilical cord blood with embryonic and hematopoietic characteristics. Zhao Y, Wang H, Mazzone T. Exp Cell Res. 2006;312:2454-2464.

Embryonic stem (ES) cells display two unique properties: self-renewal and pluripotentiality for differentiation. Stem-cell based therapy, therefore, has significant potential to cure important and common human diseases. However, a major limitation for stem cell based therapy has been identification of a suitable source of stem cells.

In this report, the authors report that they have identified a novel type of stem cell from umbilical cord blood, designated cord blood-stem cells (CB-SC). CB-SC displayed important ES cell characteristics including expression of ES-cell-specific molecular markers including transcription factors OCT-4 and Nanog, along with stage-specific embryonic antigen (SSEA)-3 and SSEA-4. CB-SC also expressed hematopoietic cell antigens including CD9, CD45 and CD117, but were negative for CD34. CB-SC displayed very low immunogenicity as indicated by expression of a very low level of major histocompatibility complex (MHC) antigens and failure to stimulate the proliferation of allogeneic lymphocytes. CB-SC can also give rise to cells with characteristics of three embryonic layers: e.g., mesoderm (endothelial-like cells), ectoderm (neuronal-like cells) and endoderm (insulin-producing cells).

The authors indicate that the most important property of CB-SC is their ability to produce a therapeutic glycemic effect in an STZ mouse model of diabetes. Accumulating evidence suggests that insulin-producing cells derived from stem cells can normalize blood glucose in diabetic animal models. However, in previous reports, these cells were derived from ES cells and fetal tissues, raising ethical concerns for theirs clinical application. The widespread availability of human cord blood underlines the potential usefulness of CB-SC for clinical therapeutics.

6. Identification of very small embryonic like (VSEL) stem cells in bone marrow. Kucia M, Wysoczynski M, Ratajczak J, Ratajczak MZ. Cell Tissue Res. 2008;331:125-134.

Bone marrow (BM) develops in mammals by the end of the second/beginning of the third trimester of gestation and becomes a major hematopoietic organ in postnatal life. The alpha-chemokine stromal derived factor-1 (SDF-1) to CXCR4 axis plays a major role in BM colonization by stem cells. By the end of the second trimester of gestation, BM becomes colonized by hematopoietic stem cells (HSC), which are chemo-attracted from the fetal liver in a CXCR4-SDF-1-dependent manner. Whereas CXCR4 is expressed on HSC, SDF-1 is secreted by BM stroma and osteoblasts that line BM cavities. Mounting evidence indicates that BM also contains rare CXCR4(+) pluripotent stem cells (PSC).

The investigators in this group have identified a population of CXCR4(+) very small embryonic like stem cells in murine BM and human cord blood. They hypothesize that these cells are deposited during development in BM as a mobile pool of circulating PSC that play a pivotal role in postnatal tissue turnover, both of non-hematopoietic and hematopoietic tissues.

7. An in vivo evidence that murine very small embryonic like (VSEL) stem cells are mobilized into peripheral blood after acute myocardial infarction (AMI) and contribute to myocardiac regeneration. Zuba-Surma EK, Kucia M, Guo Y, Dawn B, Bolli R, Ratajczak MZ. Blood 2007;110;1079A (Abstract)

The authors identified a population of SSEA-1⁺/Oct-4⁺/Sca^-1⁺/lin^-/CD45^- pluripotent, very small embryonic-like stem cells (VSEL) in adult murine bone marrow. They found that VSEL possess the ability to differentiate in vitro into all three germ layers including cardiac lineage. However, the input of these cells in regeneration of injured tissues including infarcted myocardium was uncertain. The aim of this study was to establish if VSEL are mobilized into peripheral blood after acute myocardial infarction (AMI) and could play a potential role in myocardiac regeneration.

In vitro data indicated that VSEL were mobilized in mice that had undergone a 30-min coronary occlusion followed by reperfusion. VSEL were detectable in PB on low level under baseline conditions but increased significantly after AMI, peaking at 48h post AMI both in younger and older mice.

The authors also investigated regenerative potential of VSEL injected into infracted myocardium in vivo. Mice underwent a 30-minute coronary occlusion followed by reperfusion and, 48h later, received intramyocardial injection of vehicle, freshly sorted VSEL, or VSEL pre-differentiated in cardiomyogenic medium. At 35 days of follow up, the heart function was investigated by echocardiography. Mice in the group receiving VSEL pre-differentiated in cardiomyogenic medium exhibited improved function of infarcted left ventricle showing higher LV ejection fraction. Other parameters including infarct wall thickening fraction and end-diastolic volume also indicated improvement of heart function. Thus, VSEL are not only mobilized from the bone marrow into the peripheral blood after AMI, but also participate in regenerative processes of infracted myocardium.

8. Embryonic-like stem cells from umbilical cord blood and potential for neural modeling. McGuckin C, Forraz N, Baradez MO, Basford C, Dickinson AM, Navran S, Hartgerink JD. Acta Neurobiol Exp. 2006;66:321-329.

The authors point out that umbilical cord blood (UCB) is a valuable source of stem cells in terms of access and supply. They state that they have proved that cells exist in UCB that have multi-tissue differentiation capability. To do this, they optimized a series of stringent and rapid cell separation methods whereby sequential immunomagnetic removal of mature cells in UCB combined to standardized subculture protocols reproducibly revealed immature stem cell groups with embryonic characteristics. They call these cells cord blood derived embryonic-like stem cells (CBE’s) since they were found to reproducibly express markers contiguous with embryonic stem cells. They have also repeated the work on frozen cord blood units thus removing the doubt that such cells could be produced from currently cryopreserved CB units worldwide. The authors suggest that their methods developing CBE’s may now enable preliminary expansion of the primitive CBE stem cells prior to differentiation into neural progenitors and differentiated tissues.

In summary, cord blood has a long history of successful transplantation for hematological and immune system diseases and now with the multipotentiality confirmed in vitro to produce tissues from all three human germ layers, ectodermal, endodermal and mesodermal, demonstrates that it has viability for the regenerative medicine arena.

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