Neurology India
menu-bar5 Open access journal indexed with Index Medicus
  Users online: 3760  
 Home | Login 
About Editorial board Articlesmenu-bullet NSI Publicationsmenu-bullet Search Instructions Online Submission Subscribe Videos Etcetera Contact
  Navigate Here 
 Resource Links
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
    Article in PDF (316 KB)
    Citation Manager
    Access Statistics
    Reader Comments
    Email Alert *
    Add to My List *
* Registration required (free)  

  In this Article

 Article Access Statistics
    PDF Downloaded98    
    Comments [Add]    
    Cited by others 4    

Recommend this journal


Table of Contents    
Year : 2011  |  Volume : 59  |  Issue : 2  |  Page : 226-228

Human umbilical cord blood-derived mesenchymal stem cells and their effect on gliomas

Professor of Neuropathology, Department of Neuropathology, National Institute of Mental Health and Neuro Sciences, Bangalore, India

Date of Submission17-Mar-2011
Date of Decision17-Mar-2011
Date of Acceptance17-Mar-2011
Date of Web Publication7-Apr-2011

Correspondence Address:
S K Shankar
Professor of Neuropathology, Department of Neuropathology, National Institute of Mental Health and Neuro Sciences, Bangalore-560 029
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.79126

Rights and Permissions

How to cite this article:
Shankar S K. Human umbilical cord blood-derived mesenchymal stem cells and their effect on gliomas. Neurol India 2011;59:226-8

How to cite this URL:
Shankar S K. Human umbilical cord blood-derived mesenchymal stem cells and their effect on gliomas. Neurol India [serial online] 2011 [cited 2020 Jul 8];59:226-8. Available from:

Glioblastoma in adults and pediatric brain tumors have become one of the favored vehicles for cancer stem cell hypothesis. There is compelling evidence that human glioblastoma is a heterogeneous tumor composed of lineage committed tumor cells and a subpopulation of cancer stem cells. These tumor-initiating stem cells have a high tumorogenic potential and low proliferationrate. [1],[2],[3],[4],[5] Glioma stem cells are found to be essentially similar to normal stem cells expressing CD133 stem cell marker. Cancer stem cells derived from human tumors and cell lines are capable of recapitulating original polyclonal tumor when transplanted into immunodeficient nude mice, indicating the synergistic influence of immune suppression on tumor implantation. It is well recognized that cancer stem cells can be enriched and harvested from many human tumor biopsy specimens using the CD133 (Prominin - 1) as a cell surface marker. Yet a subpopulation of CD133 negative stem cells exist with low turnover rate and tumorogenic propensity. [4],[6],[7] These cancer stem cells contribute to tumor radio/chemo resistance by an increase in DNA repair capacity through preferential activation of DNA damage response check points. [8] Bao et al, have shown that L1CAM (neural cell adhesion molecules - L1, CD 171, which regulates neural cell growth, survival, migration, axonal outgrowth and neurite outgrowth) is essential for growth and survival of CD133 positive glioma stem cells, both in vivo and in vitro, thus suggesting to be a possible therapeutic target to suppress the tumor growth. [9]

Prior to the discovery of replication competent neural progenitor/stem cells in the postnatal brain [10] mature astrocytes or committed astrocyte progenitors were thought to be the only cells capable of replication in the post natal brain and thus susceptible for malignant transformation. Although this concept is doubted, it is now shown that a genetic cocktail of a few transcription factors can convert normal mature skin cells to totipotent embryonic stem cells [11] and a tumor. Targeting the early cortical astrocytes with oncogenes or activated signal-generating proteins can produce tumors in animals. These transformation competent astrocytes can be generated from neonatal cortex, but not from the adult cortex. [12] Brain tumors formed from these stem cells not only form masses, but also infiltrate deep along fiber tracts and form small tumorlets detached from the main tumor body. Because of this wide unpredictable distribution of neoplastic cells, stem cell therapy needs to seek these neoplastic cells and destroy them without damage to neighbouring normal cells. Scientists have shown that certain adult stem cells, neural, mesenchymal or endothelial cells have an uncanny ability to home to cancers, even traveling through distant areas of the body. [13]

Having shown the capacity of the stem cells to migrate far and home to tumor cells, the next logical approach was to deliver a pay load of tumor-destroying molecules as adjuncts to chemotherapeutic agents. Cancer killing viruses, genes encoding antitumor cytokines like 1L-12, Interferon-b, 'pro-drug converting enzymes' have been engineered into engraftable neural stem cells. Having tested in animal models, neural stem cells engineered with TRAIL for proapoptotic effect or 1L-12 for antiangiogenic effect, they form potential therapeutic agents. [14]

Human mesenchymal stem cells (MSCs) are nonhemopoietic adult stem cells with multipotent capabilities. MSCs have the capacity to home to the site of tissue injury, easily transfectable and relatively non immunogenic [15],[16],[17] though the mechanism of immunogenic privilege is not well understood. [18] Some studies suggested that stromal cells surrounding epithelial tumors, far from being innocent bystanders promote the growth of adjacent transformed neoplastic cells. [19] Another study suggested that through their immune suppressive effect, their enhance tumor growth in vivo.[20] In studies on chronic limb ischemia models, the MSCs were found to produce proangiogenic cytokines enhancing angiogenesis. [21] Contrary to general expectation, when transplanted the MSCs were found to be antitumor and antiangiogenic even in angiomatous tumors like cutaneous Kaposi's sarcoma. These MSCs evaluated were derived from bone marrow of voluntary healthy young adults. [22] Human unbilical cord blood is a rich source of both hemopoietic stem cells and MSCs, with high proliferation and expansion potential than adult bone marrow-derived cells. [23]

Kang et al, have for the first time demonstrated cytotoxic ability of human umbilical cord-derived MSCs on human malignant glioma cells in vitro.[24] They also observed that human umbilical cord-derived MSCs when activated by 1L - 15, granulocyte-macrophage stimulating factor and in combination, exerted greater cytotoxic effect. They ascribed the cytotoxic effect to immune response-related proteins secreted from the MSCs following activation. Ho et al, from National Cancer Centre, Singapore, have noticed interestingly different MSCs isolated from different sources displayed differential migration ability toward human glioma cells. Highly migrating MSCs cells had higher expression of genes regulating matrix metalloprotease [1] in contrast to the ones with low migrating potential. Functional abrogation of the transcription levels of MMP1 has aborted the migratory potential towards glioma cells. Conversely conditioned medium from the highly migrating MSCs or the presence of recombinant MMP1 can rescue the non migratory phenotype of MSCs to the functional activity. [25] Interestingly expression of MMP1 at remote areas also made the nonmigratory MSCs responsive to the signaling cues from the glioma cells. Blocking the interaction of the MMPI and its receptor PAR1 effectively diminished the migratory potential. These observations strongly support the idea that matrix metalloproteases in the interstitium are critically involved in the migration of the MSCs [25] as well as the cancer cells.

Having realized the migrating and homing potential of MSCs and neural stem cells and not integrating into nonmalignant tissues, investigators started evaluating the therapeutic usefulness of various sources of these cells. Murphy, et al, realizing the pitfalls in using autologous bone marrow stem cells to induce angiogenesis in cases of 'critical limb ischemia' tried endometrial regenerative cells (mesenchymal-like stem cells) derived from menstrual blood, because of their angiogenic potential in the endometrium. [26] These mesenchymal-like endometrial stromal cells have high levels of matrix metalloproteases, and trophic factors, which can inhibit inflammation and manifest low immunogenicity and lack tumorgenicity. Having realized the potential of homing to the tumor and not to the normal parenchyma around, the search for suitable MSCs have been initiated to use these as therapeutic targets only to deliver tumor suppressor molecules, cytokines, genetic modulators and drugs. Serendipitously, to the utter surprise of the investigators, the angiogenic MSCs in critical limb ischemia were found to of low angiogenic potential and yet cytotoxic to glioma cells in vivo and in vitro. This has transformed into a field of intense study for the treatment of brain tumors. Kang et al, showed significant cytotoxicity to U87MG human malignant glioma cell line in vitro, with or without activation by cytokines. [24] In this issue of Neurology India Yang et al, from have utilized human umbilical cord blood-derived MSCs to demonstrate the cytotoxic effect on highly malignant C 6 cell line implanted in the flank of mice, following intravenous or intratumoral injection of stromal cells. Thomas E Ichem from California on the other hand, injecting endometrial regenerative cells by intravenous and intratumoral route into intracerebrally implanted aggressive C 6 - glioma cells showed tumor regression and reduced angiogenesis and reduced number of CD133 positive glioma tumor cells. [27] The important message of the studies is the ability to target the intracranial tumors by intravenous administration of MSCs derived from different sources without entering the cranium.

The mechanics of cytotoxicity of these MSCs appears to be divergent. In the case of Kaposi sarcoma, an angiogenic AIDS associated neoplastic lesion, inhibition of Akt pathway (which requires cell to cell contact between the neoplastic cells and the MSCs mediated through E-Cadherin is essential for antitumorogenic effect. [22] On the other hand, the cytotoxic effect of umbilical cord mesenchymal cells appears to be mediated by down regulation of Cyclin D 1 (as demonstrated in the article published in this issue) whose expression correlated with degree of malignancy, tumor progression and invasion. In addition enhanced production of immune response related proteins secreted by the MSCs following stimulation by cytokines indicate participation of autocrine and paracrine mechanisms in mediating cytotoxicity.

Although the potential of using MSCs derived from various sources to suppress and kill the glioma stem cells is encouraging, all the workers uniformly indicated that more work is needed to understand the basic biology and possible potential of adverse biological effects in the long term. Because of the homing property of MSCs to the site of injury, Andreef cautioned that "patients receiving the MSCs as a therapeutic modality, could not have recent surgery, pneumonia, catheters or wounds, [14] as the injected progenitor cells are found to share the tumor homing potential of MSCs. Labeling these endothelial cells with supermagnetic iron oxide nanoparticles and infusing them into mice and imaging by MRI, revealed the incorporation of the bone marrow-derived endothelial cells into areas of neovascularisation but not to quiescent vessels. This observation forms another potential drug delivery target and studying the progression of tumor by imaging.[29]

As a scientific study, various observations are exciting and have tremendous potential. However, it takes some more time before the MSC transfusion becomes a useful therapeutic strategy to human subjects.

  References Top

1.Stiles CD, Rowitch DH. Glioma stem cells: a midterm exam. Neuron 2008;58:832-46.  Back to cited text no. 1
2.Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res 2003;63:5821-8.  Back to cited text no. 2
3.Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, et al. Identification of human brain tumour initiating cells. Nature 2004;432:396-401.  Back to cited text no. 3
4.Bao S, Wu Q, Sathornsumetee S, Hao Y, Li Z, Hjelmeland AB, et al. Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res 2006;66:7843-8.  Back to cited text no. 4
5.Pollard SM, Yoshikawa K, Clarke ID, Danovi D, Stricker S, Russell R, et al. Glioma stem cell lines expanded in adherent culture have tumor-specific phenotypes and are suitable for chemical and genetic screens. Cell Stem Cell 2009;4:568-80.  Back to cited text no. 5
6.Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, De Vitis S, et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 2004;64:7011-21.  Back to cited text no. 6
7.Beier D, Hau P, Proescholdt M, Lohmeier A, Wischhusen J, Oefner PJ, et al. CD133(+) and CD133(-) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res 2007;67:4010-5.  Back to cited text no. 7
8.Altaner C. Glioblastoma and stem cells. Neoplasma 2008;55:369-74.   Back to cited text no. 8
9.Bao S, Wu Q, Li Z, Sathornsumetee S, Wang H, McLendon RE, et al. Targeting cancer stem cells through L1CAM suppresses glioma growth. Cancer Res 2008;68:6043-8.  Back to cited text no. 9
10.Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science 1992;255:1707-10.  Back to cited text no. 10
11.Nakagawa M, Koyanagi M, Tanabe K, Takahashi K, Ichisaka T, Aoi T, et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol 2008;26:101-6.  Back to cited text no. 11
12.Laywell ED, Rakic P, Kukekov VG, Holland EC, Steindler DA. Identification of a multipotent astrocytic stem cell in the immature and adult mouse brain. Proc Natl Acad Sci U S A 2000;97:13883-8.  Back to cited text no. 12
13.Aboody KS, Brown A, Rainov NG, Bower KA, Liu S, Yang W, et al. Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc Natl Acad Sci U S A 2000;97:12846-51.  Back to cited text no. 13
14.Brower V. Search and destroy: Recent research exploits adult stem cells' attraction to cancer. J Natl Cancer Inst 2005;97:414-6.  Back to cited text no. 14
15.Chen J, Li Y, Wang L, Zhang Z, Lu D, Lu M, et al. Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke 2001;32:1005-11.  Back to cited text no. 15
16.Barbash IM, Chouraqui P, Baron J, Feinberg MS, Etzion S, Tessone A, et al. Systemic delivery of bone marrow-derived mesenchymal stem cells to the infarcted myocardium: Feasibility, cell migration, and body distribution. Circulation 2003;108:863-8.   Back to cited text no. 16
17.Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringdén O. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol 2003;31:890-6.  Back to cited text no. 17
18.Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 2005;105:1815-22.   Back to cited text no. 18
19.Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, Shappell S, et al. TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science 2004;303:848-51.  Back to cited text no. 19
20.Djouad F, Plence P, Bony C, Tropel P, Apparailly F, Sany J, et al. Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood 2003;102:3837-44.  Back to cited text no. 20
21.Al-Khaldi A, Al-Sabti H, Galipeau J, Lachapelle K. Therapeutic angiogenesis using autologous bone marrow stromal cells: Improved blood flow in a chronic limb ischemia model. Ann Thorac Surg 2003;75:204-9.  Back to cited text no. 21
22.Khakoo AY, Pati S, Anderson SA, Reid W, Elshal MF, Rovira II, et al. Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi's sarcoma. J Exp Med 2006;203:1235-47.   Back to cited text no. 22
23.Yang SE, Ha CW, Jung M, Jin HJ, Lee M, Song H, et al. Mesenchymal stem/progenitor cells developed in cultures from UC blood. Cytotherapy 2004;6:476-86.  Back to cited text no. 23
24.Kang SG, Jeun SS, Lim JY, Kim SM, Yang YS, Oh WI, et al. Cytotoxicity of human umbilical cord blood-derived mesenchymal stem cells against human malignant glioma cells. Childs Nerv Syst 2008;24:293-302.  Back to cited text no. 24
25.Ho IA, Chan KY, Ng WH, Guo CM, Hui KM, Cheang P, et al. Matrix metalloproteinase 1 is necessary for the migration of human bone marrow-derived mesenchymal stem cells toward human glioma. Stem Cells 2009;27:1366-75.  Back to cited text no. 25
26.Murphy MP, Wang H, Patel AN, Kambhampati S, Angle N, Chan K, et al. Allogeneic endometrial regenerative cells: An "Off the shelf solution" for critical limb ischemia? J Transl Med 2008;19:4-5.  Back to cited text no. 26
27.Jaio H, Guan F, Yang B, Li J, Shan H, Song L, et al. Human umbilical cord blood-derived mesenchymal stem cells inhibit C6 glioma via downregulation of cyclin D1. Neurol India 2011;59:241-7.   Back to cited text no. 27
28.Han X, Meng X, Yin Z, Rogers A, Zhong J, Rillema P, et al. Inhibition of intracranial glioma growth by endometrial regenerative cells. Cell Cycle 2009;8:606-10.  Back to cited text no. 28
29.Anderson SA, Glod J, Arbab AS, Noel M, Ashari P, Fine HA, et al. Noninvasive MR imaging of magnetically labeled stem cells to directly identify neovasculature in a glioma model. Blood 2005;105:420-5.  Back to cited text no. 29

This article has been cited by
1 Human mesenchymal stromal cell therapy for prevention and recovery of chemo/radiotherapy adverse reactions
Fatemeh Hendijani
Cytotherapy. 2015; 17(5): 509
[Pubmed] | [DOI]
2 Induced differentiation of umbilical cord blood mesenchymal stem cells into neuron-like cells
Chen, L. and Chen, B. and Xie, F.-t.
Chinese Journal of Tissue Engineering Research. 2012; 16(23): 4335-4338
3 In vivo hepatic differentiation of mesenchymal stem cells from human umbilical cord blood after transplantation into mice with liver injury
Yu, J. and Cao, H. and Yang, J. and Pan, Q. and Ma, J. and Li, J. and Li, Y. and Li, J. and Wang, Y. and Li, L.
Biochemical and Biophysical Research Communications. 2012; 422(4): 539-545
4 In vivo hepatic differentiation of mesenchymal stem cells from human umbilical cord blood after transplantation into mice with liver injury
Jiong Yu,Hongcui Cao,Jinfeng Yang,Qiaoling Pan,Jing Ma,Jianzhou Li,Yanyuan Li,Jun Li,Yingjie Wang,Lanjuan Li
Biochemical and Biophysical Research Communications. 2012; 422(4): 539
[Pubmed] | [DOI]


Print this article  Email this article
Online since 20th March '04
Published by Wolters Kluwer - Medknow