Publications by authors named "Chandra Viswanathan"

31 Publications

Significance of CD34 Negative Hematopoietic Stem Cells and CD34 Positive Mesenchymal Stem Cells - A Valuable Dimension to the Current Understanding.

Curr Stem Cell Res Ther 2017 ;12(6):476-483

Research & Development Team, ReeLabs Private Limited, Andheri West, Mumbai, 400 053, India.

Background: The strategy to expand CD34+ hematopoietic stem cells (HSCs) is being increasingly practiced to meet the demand for a higher cell dose. This is for hematopoietic reconstitution in patients with higher body weights. Interestingly, literature reports show that CD34- (CD34 negative) cell population also possesses the potential to reconstitute the bone marrow & in a certain phase, converts them into CD34+ phenotype. The current practice of positive selection of CD34+ HSCs by eliminating rest of the (CD34-) population for expansion could probably pose a risk of losing valuable HSCs with good reconstitution potentials. MSCs (Mesenchymal Stem Cells) hold great promise for use in various regenerative medicine applications. International Society for Cellular Therapy (ISCT) defined MSCs to be CD34 negative; tissue resident MSCs and peripheral blood-derived MSCs express CD34 on their surface even in vitro, though up to limited passages. This interesting observation of CD34 positive expression displayed in vivo by non-hematopoietic cell types such as MSCs was intriguing, thus prompting a detailed review of its significance, if any.

Objective: Based on an extensive review, we strongly believe that CD34 expression in MSCs has some significant role in hematopoietic reconstitution & in regeneration of degenerated tissues. The concept of poor CD34 expression or stunted expression by certain MSCs should not be ignored. Several interesting research findings are in agreement with our assumption. However, it still leaves behind several unanswered questions that can only be addressed through detailed studies of phenotypic developmental pathways of MSCs.
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http://dx.doi.org/10.2174/1574888X12666170502095625DOI Listing
May 2018

Cryopreserved hepatic progenitor cells derived from human embryonic stem cells can arrest progression of liver fibrosis in rats.

Cell Biol Int 2016 Oct 24;40(10):1107-15. Epub 2016 Aug 24.

Regenerative Medicine, Reliance Life Sciences Pvt. Ltd., Dhirubhai Ambani Life Sciences Centre, R-282, TTC Industrial Area of MIDC, Thane Belapur Road, Rabale, Navi Mumbai, 400701, India.

Hepatocytes generated from human embryonic stem cells (hESCs) are considered to be an excellent candidate for restoring the liver function deficiencies. We have earlier standardized a three-step differentiation protocol to generate functional hepatocyte-like cells (HLCs) from hESCs, which expressed the major hepatic markers. We have also found that the HLCs remain stable and functional even after extended period of in vitro culture and cryopreservation. In the present study, we have aimed to investigate the therapeutic potential of cryopreserved-thawed hESC-derived hepatic progenitor cells following transplantation in carbon tetrachloride-induced fibrotic rat livers. Significant therapeutic effects, including improved hepatic histology and normal serum biochemistry of hepatic enzymes along with increased survival rate, were observed in the cell transplanted rats. This result is an encouraging indication to develop methods for clinical application of hESC-derived hepatic lineage cells.
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http://dx.doi.org/10.1002/cbin.10649DOI Listing
October 2016

Umbilical Cord Derived Mesenchymal Stem Cells Useful in Insulin Production - Another Opportunity in Cell Therapy.

Int J Stem Cells 2016 May;9(1):60-9

Reliance Life Sciences Pvt Ltd., Dhirubhai Ambani Life Sciences Centre, Navi Mumbai, India.

Background And Objectives: Type 1 Diabetes Mellitus (T1DM) is an autoimmune disorder resulting out of T cell mediated destruction of pancreatic beta cells. Immunomodulatory properties of mesenchymal stem cells may help to regenerate beta cells and/or prevent further destruction of remnant, unaffected beta cells in diabetes. We have assessed the ability of umbilical cord derived MSCs (UCMSCs) to differentiate into functional islet cells in vitro.

Methods And Results: We have isolated UCMSCs and allowed sequential exposure of various inducing agents and growth factors. We characterized these cells for confirmation of the presence of islet cell markers and their functionality. The spindle shaped undifferentiated UCMSCs, change their morphology to become triangular in shape. These cells then come together to form the islet like structures which then grow in size and mature over time. These cells express pancreatic and duodenal homeobox -1 (PDX-1), neurogenin 3 (Ngn-3), glucose transporter 2 (Glut 2) and other pancreatic cell markers like glucagon, somatostatin and pancreatic polypeptide and lose expression of MSC markers like CD73 and CD105. They were functionally active as demonstrated by release of physiological insulin and C-peptide in response to elevated glucose concentrations.

Conclusions: Pancreatic islet like cells with desired functionality can thus be obtained in reasonable numbers from undifferentiated UCMSCs in vitro. This could help in establishing a "very definitive source" of islet like cells for cell therapy. UCMSCs could thus be a game changer in treatment of diabetes.
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http://dx.doi.org/10.15283/ijsc.2016.9.1.60DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4961105PMC
May 2016

Long-term culture and cryopreservation does not affect the stability and functionality of human embryonic stem cell-derived hepatocyte-like cells.

In Vitro Cell Dev Biol Anim 2016 Feb 20;52(2):243-51. Epub 2015 Oct 20.

Regenerative Medicine, Reliance Life Sciences Pvt Ltd, Dhirubhai Ambani Life Sciences Centre, R-282, TTC Industrial Area of MIDC, Thane Belapur Road, Rabale, Navi Mumbai, 400 701, India.

Human embryonic stem cells (hESCs) are predicted to be an unlimited source of hepatocytes which can pave the way for applications such as cell replacement therapies or as a model of human development or even to predict the hepatotoxicity of drug compounds. We have optimized a 23-d differentiation protocol to generate hepatocyte-like cells (HLCs) from hESCs, obtaining a relatively pure population which expresses the major hepatic markers and is functional and mature. The stability of the HLCs in terms of hepato-specific marker expression and functionality was found to be intact even after an extended period of in vitro culture and cryopreservation. The hESC-derived HLCs have shown the capability to display sensitivity and an alteration in the level of CYP enzyme upon drug induction. This illustrates the potential of such assays in predicting the hepatotoxicity of a drug compound leading to advancement of pharmacology.
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http://dx.doi.org/10.1007/s11626-015-9956-1DOI Listing
February 2016

Preparation and characterization of silver nanoparticle loaded amorphous hydrogel of carboxymethylcellulose for infected wounds.

Carbohydr Polym 2015 Oct 7;130:254-61. Epub 2015 Apr 7.

Department of Tissue Engineering & Wound Management, Regenerative Medicine, Reliance Life Sciences, Rabale, Navi Mumbai, Maharashtra 400701, India. Electronic address:

There is a growing demand for an appropriate and safe antimicrobial dressing to treat infected deep wounds. An amorphous gel formulation (SNP-CMC), containing silver nanoparticles (SNPs) and carboxymethylcellulose (CMC), was prepared in one step by the reduction of silver nitrate in situ. Spectrophotometric and microscopic analysis revealed that the SNPs were 7-21 nm in diameter. In simulated wound experiments, SNP-CMC gel was found to absorb 80.48 ± 4.69% w/w of saline and donate 17.43 ± 0.76% w/w of moisture within 24h indicating its dual fluid affinity. Cytocompatibility of the gel was assessed by proliferation studies with primary human skin cells. The antimicrobial activity studies showed that SNP-CMC containing 50 ppm of SNPs was effective against the growth of both Gram negative and Gram positive strains including methicillin-resistant Staphylococcus aureus (MRSA). These results indicate that SNP-CMC could be ideal for the treatment of deep infected wounds.
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http://dx.doi.org/10.1016/j.carbpol.2015.03.082DOI Listing
October 2015

Potential of Mesenchymal Stem Cell based application in Cancer.

Int J Hematol Oncol Stem Cell Res 2015 Apr;9(2):95-103

Regenerative Medicine Group, Reliance Life Sciences Pvt. Ltd. Dhirubhai Ambani Life Sciences Centre, R-282, TTC Area of MIDC, Thane-Belapur Road, Rabale, Navi Mumbai - 400701. India.

Stem cell based treatments are being increasingly explored for their possible potential to treat various cancers. Mesenchymal stem cells believed to possess anti-tumor potential and are preferred for their properties like immune privileged nature, ability to migrate to the site of tumor and capability for multilineage differentiation. This tumor tropism property of MSCs could be utilized to deliver anti-tumor biological agents to the site of tumor. In a tumor micro-environment, MSCs are believed to play both, a pro-tumorigenic and an anti-tumorigenic role. However, this is dependent on a host of factors like, types of MSCs, its source, type of cancer cell line under investigation, in vivo or in vitro conditions, factors secreted by MSCs and interactions between MSCs, host's immune cells and cancer cells. Among several cytokines secreted by MSCs, TRAIL (Tumor necrosis factor related apoptosis inducing ligand) is reported to be pro-apoptotic for tumor cells. The MSCs from bone marrow and adipose tissue have been studied quite extensively. Deriving MSCs from sources such as umbilical cord blood and umbilical cord tissue is relatively easier. Umbilical cord tissue preferred for MSC derivation due to their abundant availability. These MSCs believed to up regulate TRAIL expression in MSC-cancer cell co-culture system resulting in induction of apoptosis in cancer cells. However, umbilical cord tissue derived MSCs needs to be studied for expression pattern of TRAIL in a co-culture system. We present a review article on different studies reporting both, pro-tumorigenic and anti-tumorigenic properties of MSCs.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4410295PMC
April 2015

Transplantation of Autologous Ex Vivo Expanded Human Conjunctival Epithelial Cells for Treatment of Pterygia: A Prospective Open-label Single Arm Multicentric Clinical Trial.

J Ophthalmic Vis Res 2014 Oct-Dec;9(4):407-16

Regenerative Medicine Group, Reliance Life Sciences Pvt. Ltd., Navi Mumbai, Maharashtra, India.

Purpose: To establish the efficacy and safety of ex vivo cultured autologous human conjunctival epithelial cell (hCjEC) transplantation for treatment of pterygia.

Methods: Twenty-five patients with pterygia were recruited at different centers across the country. Autologous hCjEC grafts were prepared from conjunctival biopsy specimens excised from the healthy eye and cultured ex vivo on human amniotic membrane mounted on inserts using a unique mounting device. The hCjEC grafts were then transported in an in-house designed transport container for transplantation. Post-surgery, the patients were followed up on days 1, 7, 14, 30, 90, and 180 as per the approved study protocol. Clinical outcomes were assessed by slit lamp examination, visual acuity, imprint cytology, fluorescein/rose bengal staining, Schirmer's test, and photographic evaluation three and 6 months post-transplantation.

Results: Two patients were lost to follow-up and final analysis included 23 cases. No recurrence of pterygium was observed in 18 (78.3%) patients; all of these eyes showed a smooth conjunctival surface without epithelial defects. Recurrence was observed in 5 (21.7%) patients at 3 months post-treatment. No conjunctival inflammation, secondary infections or other complications were reported. Adequate goblet cells were present in 19 (82.6%) patients at the site of transplantation.

Conclusion: We have, for the 1(st) time, standardized a protocol for preparing autologous hCjEC grafts that can be safely transported to multiple centers across the country for transplantation. The clinical outcome was satisfactory for treating pterygia.
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http://dx.doi.org/10.4103/2008-322X.150800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4329698PMC
February 2015

Natural killer cells: In health and disease.

Hematol Oncol Stem Cell Ther 2015 Jun 27;8(2):47-55. Epub 2014 Dec 27.

Regenerative Medicine, Reliance Life Sciences Pvt Ltd, Dhirubhai Ambani Life Sciences Centre, R-282, TTC Industrial Area of MIDC, Thane Belapur Road, Rabale, Navi Mumbai 400 701, India. Electronic address:

Natural killer (NK) cells constitute our bodies' frontline defense system, guarding against tumors and launching attacks against infections. The activities of NK cells are regulated by the interaction of various receptors expressed on their surfaces with cell surface ligands. While the role of NK cells in controlling tumor activity is relatively clear, the fact that they are also linked to various other disease conditions is now being highlighted. Here, we present an overview of the role of NK cells during normal body state as well as under diseased state. We discuss the possible utilization of these powerful cells as immunotherapeutic agents in combating diseases such as asthma, autoimmune diseases, and HIV-AIDS. This review also outlines current challenges in NK cell therapy.
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http://dx.doi.org/10.1016/j.hemonc.2014.11.006DOI Listing
June 2015

Paracrine factors secreted by umbilical cord-derived mesenchymal stem cells induce angiogenesis in vitro by a VEGF-independent pathway.

Stem Cells Dev 2015 Feb 3;24(4):437-50. Epub 2014 Nov 3.

Tissue Engineering Group, Regenerative Medicine, Reliance Life Sciences Pvt. Ltd. , Navi-Mumbai, Maharashtra, India .

Improvement in angiogenesis using mesenchymal stem cells (MSCs) is evolving as an option in patients with vascular insufficiencies. The paracrine factors secreted by MSCs have been attributed to the angiogenic response. This study was conducted to identify the factors secreted by umbilical cord-derived MSCs (UCMSCs) that might play a role in angiogenesis. To this aim, we evaluated the presence of well known proangiogenic factors in the conditioned media (CM) derived from UCMSCs by ELISA. While vascular endothelial growth factor (VEGF), a well known angiogenic factor, was not detected in the CM, gene expression was nevertheless detected in these cells. Further investigations revealed the presence of soluble VEGF receptors (sVEGF-R1 and R2) that were capable of neutralizing exogenous VEGF. Human umbilical cord vein-derived endothelial cells exposed in vitro to CM, in comparison to control media, showed improved migration (P<0.007) and capillary-like network formation (P<0.001) with no significant change in endothelial cell proliferation. The angiogenic response observed with the paracrine factors secreted by UCMSC could be due to the presence of significant levels of a metalloprotease and matrix metalloproteases-2 (237.4±47.1 ng/10(6) cells). Data suggest that a VEGF-independent pathway is involved in the angiogenic response observed with endothelial cells in the presence of UCMSC-CM.
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http://dx.doi.org/10.1089/scd.2014.0184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4313407PMC
February 2015

Defining Permissible Time Lapse between Umbilical Cord Tissue Collection and Commencement of Cell Isolation.

Int J Hematol Oncol Stem Cell Res 2013 ;7(4):15-23

Regenerative Medicine Group, Reliance Life Sciences Pvt. Ltd., Dhirubhai Ambani Life Sciences Centre, R-282, TTC Area of MIDC, Thane-Belapur Rd. Rabale, Navi Mumbai - 400701, Maharashtra, India.

Background: Umbilical cord tissue is a very rich source of mesenchymal stem cells. Instead of discarding this source we are banking the tissue along with cord blood for possible future cell based applications. The cord tissue needs to be transported and stored properly in order for it to be good enough for cell isolation at a later date. In this paper we have carried out a validation study to determine the maximum permissible time between cord tissue collection and beginning of cell culture process under defined conditions of temperature and collection media.

Methods: Ten cord tissue samples were used for this study. The umbilical cord tissue segments were transported and stored at 2 - 8°(C) for varying periods of time viz. 04, 11, 22 and 30 days in a defined medium after which MSCs were isolated and characterized by flow cytometry. Karyotypic studies were also performed on the isolated cells at the above time points.

Results: MSCs could be successfully isolated from 09 even samples after a storage period of 22 days and from 07 samples after a period of 30 days from the date of collection. There was no change in the morphology, immunophenotye, karyotypye and growth potential of the cells isolated from cord tissue after the maximum storage period of 30 days.

Conclusion: The umbilical cord tissue is stable for as long as 22 days if stored at the recommended storage conditions of 2 - 8°(C) in the defined medium.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3915426PMC
February 2014

A non-invasive method to evaluate the efficacy of human myoblast in botulinum-A toxin induced stress urinary incontinence model in rats.

Urol J 2014 Jan 4;10(4):1126-34. Epub 2014 Jan 4.

Tissue Engineering Group, Regenerative Medicine, Reliance Life Sciences Pvt.

Purpose: To develop a simple non-invasive method to assess the efficacy of a cell based therapy for treating stress urinary incontinence (SUI).

Materials And Methods: In this study, skeletal myoblasts were used as candidate therapy to reverse SUI. The SUI model was created in rats using periurethral injection of botulinum-A toxin injection. Two weeks later, the rats were administered saline and the level of continence in each botulinum-A toxin treated and control animals was assessed by the extent of voiding using metabolic cages. To determine the efficacy of myoblasts to reverse SUI, botulinum-A toxin treated incontinent rats were injected with either cultured human skeletal myoblasts or with buffered saline (sham control). Two weeks post implantation, the extent of continence was evaluated as mentioned above.

Results: The difference in void volume between botulinum-A toxin -treated and control rats were significant. Histological analysis of the urethra showed remarkable atrophy of the muscular layer. A significant reversal (P = .025) in the volume of voiding was observed in cell-implanted rats as compared to sham injected rats. Histological analysis of the urethra implanted with myoblasts showed recovery of the atrophied muscular layer in comparison to sham control. Immunofluorescence analysis of the cell injected tissues confirmed the presence of human myoblasts in the regenerated area.

Conclusion: This simplified method of in vivo testing can serve as a tool to test the efficacy of new therapies for treating SUI.
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January 2014

Status of stem cell based clinical trials in the treatment for diabetes.

Curr Diabetes Rev 2013 Nov;9(6):429-36

Reliance Life Sciences Pvt Ltd., Dhirubhai Ambani Life Sciences Centre, R/282, MIDC area of TTC, Thane Belapur Road, Rabale, Navi Mumbai 400701, India.

Rapidly increasing number of diabetic patients across the world is a great challenge to the current therapeutic approach. Although the traditional method of rendering exogenous insulin is an established method of treatment, it is not sufficient and often causes lethal hypoglycemia. There is also a good amount of success with whole organ transplantation or Islet cells' transplantation. But this technique is limited with regards the availability of donors. Currently, many clinicians and researchers are involved in clinical studies using various different stem cells from embryonic as well as adult sources for the treatment of diabetes. In this review we have tried to discuss the results of various clinical trials using stem cells. We have also tried to look at various stem cell types and the routes of injections that are currently being followed world wide.
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http://dx.doi.org/10.2174/15733998113096660082DOI Listing
November 2013

Dopaminergic cells, derived from a high efficiency differentiation protocol from umbilical cord derived mesenchymal stem cells, alleviate symptoms in a Parkinson's disease rodent model.

Cell Biol Int 2013 Feb;37(2):167-80

Regenerative Medicine, Reliance Life Sciences Pvt Ltd, Dhirubhai Ambani Life Sciences Centre R-282, TTC Industrial Area of MIDC, Thane Belapur Road, Rabale, Navi, Mumbai 400701, India.

Mesenchymal stem cells (MSCs) could be an alternative to foetal cells in the treatment of several neurodegenerative diseases, especially Parkinson's disease (PD). We have previously demonstrated the functional efficacy of the undifferentiated bone marrow MSCs (BMMSCs) cultured in a xenofree conditions in PD animal models. We now demonstrate isolation of MSCs from the umbilical cord matrix tissue and assess their safety and efficacy to improve Parkinsonian symptoms in an in vivo animal model. The efficacy of MSCs from BM and umbilical cord in the PD animal mode has also been studied, and more importantly the efficacy of using differentiated UCMSC (D-UCMSCs) to dopaminergic phenotype. Phenotypically, UCMSCs expressed higher levels of SSEA4 compared to BMMSCs. Analysis of differentiated cells showed that D-UCMSCs expressed significant levels of Tyrosine Hydroxyalse and Nurr1 compared to D-BMMSCs. The in vivo efficacy of the differentiated and undifferentiated cell types in the Parkinsonian rats showed that D-UCMSCs improved the symptoms throughout a year of study. Differentiated cell types are potentially better for clinical use than the undifferentiated type, provided they are made available at the site of action in adequate numbers. MSCs are less immunogenic and immunomodulatory, which opens up the further possibility of using these cells in allogeneic settings. This could be a novel cell therapy application, especially when getting autochthonous cells is difficult.
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http://dx.doi.org/10.1002/cbin.10029DOI Listing
February 2013

Establishment, characterization, and differentiation of a karyotypically normal human embryonic stem cell line from a trisomy-affected embryo.

In Vitro Cell Dev Biol Anim 2013 Jan 14;49(1):15-26. Epub 2012 Dec 14.

Regenerative Medicine, Reliance Life Sciences Pvt Ltd, Dhirubhai Ambani Life Sciences Centre, R-282, TTC Industrial Area of MIDC, Thane Belapur Road, Rabale, Navi Mumbai, 400 701, India.

Derivation of human embryonic stem cell (hESC) lines from chromosomally or genetically abnormal embryos obtained following preimplantation genetic diagnosis (PGD) is of immense interest to study various kinds of genetic disorders. In this study, we have established a new hESC line Relicell(®)hES4, isolated from an aneuploid embryo. Derivation of this cell line was achieved by isolation of the inner cell mass (ICM) by mechanical method. Karyotype analysis showed that the hESC line is euploid having 46 chromosomes, contrary to our expectations. The undifferentiated cells exhibited long-term proliferation capacity and expressed markers typical for hESC, such as OCT4, NANOG, and SSEA4. A comparative microarray study was carried out to analyze the transcription profile of Relicell(®)hES4 along with three other normal hESC line generated earlier in our lab. Relicell(®)hES4 manifested pluripotent differentiation potential both in vivo and in vitro. The cells were also induced to form neurons, cardiomyocytes, and pancreatic β islets. The generation of a normal hESC line from an abnormal embryo points to the fact that even such embryos can be considered for deriving new hESC lines instead of discarding them. The data represented here are the first detailed report on characterization and differentiation of an Indian hESC line generated from a PGD analyzed embryo.
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http://dx.doi.org/10.1007/s11626-012-9567-zDOI Listing
January 2013

In vitro and in vivo evaluation of (L)-lactide/ε-caprolactone copolymer scaffold to support myoblast growth and differentiation.

Biotechnol Prog 2013 Jan-Feb;29(1):197-205. Epub 2012 Dec 20.

Tissue Engineering Group, Regenerative Medicine, Reliance Life Sciences Pvt. Ltd., 282-TTC Area of MIDC, Rabale, Navi-Mumbai, Maharashtra, India 400701.

Skeletal muscle regeneration involves the activation of satellite cells to myoblasts, followed by their proliferation and fusion to form multinucleated myotubes and myofibers. The potential of in vitro proliferated myoblasts to treat various diseases and tissue defects can be exploited using tissue-engineering principles. With an aim to develop a biocompatible and biodegradable scaffold that supports myoblast growth and differentiation, we have developed a porous sponge with 70/30 L-lactide/ε-caprolactone copolymer (PLC) using a phase inversion combined with particulate leaching method. Degradation studies indicated that the sponge retained its structural integrity for 5 months in vitro and had undergone complete biodegradation within 9 months in vivo. The sponge supported human myoblasts attachment and its proliferation. Myoblasts seeded on the PLC sponge differentiated and fused in vitro to form myotubes expressing myosin heavy chain. Histological and molecular analyses of the PLC scaffolds seeded with green fluorescent protein-labeled human myoblasts and implanted ectopically under the skin in SCID mice demonstrated the presence of multinucleated myotubes expressing human muscle-specific markers. Our results suggest that PLC sponges loaded with myoblasts can be used for skeletal muscle engineering or for inducing muscle repair.
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http://dx.doi.org/10.1002/btpr.1665DOI Listing
January 2014

Radiolabeling of umbilical cord-derived mesenchymal stem cells for in vivo tracking.

Cancer Biother Radiopharm 2012 Nov 9;27(9):614-9. Epub 2012 Oct 9.

Radiopharmaceuticals Division, Bhabha Atomic Research Centre, Mumbai, India.

Non-invasive methods for the assessment of distribution, homing, and retention of stem cells are desired for the successful demonstration of stem cell therapy. Cells labeled with (99m)Tc, (18)F, and (111)In have been reported for tracking the cells in vivo. However, they can be tracked only for a limited time due to the short half lives of these isotopes. In this context, stem cells labeled with (51)Cr would be appropriate for tracking cells for a longer period of time owing to their half life of 27.7 days. Here, we have isolated mesenchymal stem cells (MSCs) from umbilical cord tissue, characterized them, and attempted to radiolabel them with (51)Cr for mapping the fate of transplanted MSC cells after an intravenous injection via the tail vein in small animals.
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http://dx.doi.org/10.1089/cbr.2011.1146DOI Listing
November 2012

Efficacy and safety of autologous cultured melanocytes delivered on poly (DL-lactic acid) film: a prospective, open-label, randomized, multicenter study.

Dermatol Surg 2012 Dec 1;38(12):1981-90. Epub 2012 Oct 1.

Tissue Engineering Group, Regenerative Medicine, Navi Mumbai, India.

Background: Small vitiliginous patches have been treated with epidermal grafts or their cell suspensions. In an attempt to overcome some of the shortcomings of cell suspension delivery, we have delivered melanocytes on a polymeric film.

Objectives: To evaluate the clinical effectiveness of a cultured graft consisting of autologous cultured melanocytes on a poly (DL-lactic acid) (PLA) film in subjects with stable vitiligo.

Methods: A prospective open-label, randomized, multicenter clinical trial was conducted with 22 patients. Each subject was treated with cultured graft and polyurethane dressing (control arm) after epidermal ablation and followed for up to 9 months. The extent of repigmentation in the treated sites was compared with that control sites at days 90, 180, and 270.

Results: In the treatment arm, a minimum of 70% repigmentation was observed in five subjects at day 90; nine at day 180, and 10 at day 270. In the control arm, only one subject showed repigmentation until day 270. None of the test sites reported any recurrence of vitiliginous patches by the end of the study.

Conclusions: Cultured melanocytes delivered on PLA film were efficacious and safe when applied on patients with stable vitiligo.
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http://dx.doi.org/10.1111/dsu.12000DOI Listing
December 2012

Establishment of a mesenchymal stem cell bank.

Stem Cells Int 2011 4;2011:905621. Epub 2011 Aug 4.

Reliance Life Sciences Pvt. Ltd., Dhirubhai Ambani Life Sciences Centre, R-282, TTC Area of MIDC, Thane-Belapur Road, Rabale, Navi Mumbai, Maharashtra-400701, India.

Adult stem cells have generated great amount of interest amongst the scientific community for their potential therapeutic applications for unmet medical needs. We have demonstrated the plasticity of mesenchymal stem cells isolated from the umbilical cord matrix. Their immunological profile makes it even more interesting. We have demonstrated that the umbilical cord is an inexhaustible source of mesenchymal stem cells. Being a very rich source, instead of discarding this tissue, we worked on banking these cells for regenerative medicine application for future use. The present paper gives a detailed account of our experience in the establishment of a mesenchymal stem cell bank at our facility.
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http://dx.doi.org/10.4061/2011/905621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150152PMC
November 2011

Optimization of the inventory size of the public cord blood program--the Indian context.

J Assoc Physicians India 2010 Oct;58:608-11

Reliance Life Sciences Dhirubhai Ambani Life Science Center, R-282, TTC Area of MIDC, Thane-Belapur Rd., Rabale, Navi Mumbai-400701, Maharashtra, India.

Background: There are reportedly more than 250,000 cord blood units [CBU] available in cord blood banks world over, yet, there are many who are unable to get a suitable match. Being the pioneer to set up the first and only public cord blood bank in India, we needed to strategize the pool size that will meet the transplantation needs of the people of Indian origin, worldwide.

Purpose: To define the optimum size of this public cord blood repository [CBR] that will give at least one 5/6 HLA match to a defined number of cord blood graft requests.

Methods: We checked the trend of human Leukocyte antigen [HLA] match graft offerings, to 112 random requests from a database of 1800 CBUs. The HLA match function was performed using an 'in house' built and validated software. The pattern of availability of the matches was used as the basis of our study. We then performed a probability analysis to check the probable pool size that would offer at least one acceptable match to all the 112 requests.

Results: With an inventory of 1800 units, we could offer 4/6 matches to about 99% and 5/6 matches to approximately only 29% and 6/6 matches to only 7% of the 112 random requests. Thus, acceptable matches were offered to about 30% of the requests received in the period and database considered for this study.

Conclusion: By employing probability analysis, we concluded that, by doubling the size, we will probably offer at least one 5/6 match to each requester, and from a pool size of about 55500 grafts, we may offer a full house (6/6 match) to the same number of requisitions. Genetic homology between the recipient and donor base, increases the probability of match availability. A good ethnic representation of the Indian population in our CBR plays a significant role in match availability.
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October 2010

Tansplantation of autologous bone marrow derived mesenchymal stem cells trans-epicardially in patients undergoing coronary bypass surgery.

Indian Heart J 2010 Jan-Feb;62(1):43-8

Institute of Cardio-Vascular Diseases, The Madras Medical Mission, Mogappair, Chennai, Tamil Nadu, India.

Background: Myocardial Infarction (MI) hampers cardiac performance by ventricular remodeling which is a major cause of heart failure or death. Conventional drug therapies like beta blockers, angiotensin-converting enzyme may delay remodeling but there is no single therapeutic regimen available that can prevent or reverse the process of myocardial injury. Interventional therapies and surgical procedures improve or normalize coronary blood flow greatly. Experimental data suggests that bone marrow derived Mesenchymal Stem Cells (MSCs) may contribute to the healing of Myocardial infarction. We present our findings on the use of bone marrow derived MSCs for Myocardial Infarction wherein the cells were injected in and around the infarct region epicardially during coronary bypass surgery.

Methods & Materials: 31 patients selected to undergo Coronary Artery Bypass Graft (CABG) as a treatment option for myocardial infarction formed the subject matter of our study. One patient withdrew consent before receiving our therapy and was excluded from the study. 15 patients (all men, average age 57) formed the test arm who underwent CABG plus Bone Marrow Mesenchymal Stem Cells (BMMSCs) transplantation whereas another 15 patients underwent conventional CABG only (14 men and 1 woman, mean age 57) served as the control arm. The cell transplantation consisted of injecting BMMSCs in the border zone of the clearly visible infarcted area transepicardially. The absolute number of MSCs injected ranged between 3 million and 26 million cells.

Results: The data for change from baseline in the area of infarct was collected at 3 months and 6 months during the study and analyzed using paired t-tests. The mean percentage perfusion improvement from baseline in the area of infarct supplied by the Left Anterior Descending Artery (LAD) was higher in the cases (35.8%) as compared to the controls (11.3%) at 3 months post treatment (p value < 0.05). There were three cases of arrhythmia, and none of the adverse events recorded were due to the investigational product. Improvement in the ejection fraction was similar in the cases and controls.

Conclusions: This study demonstrates that trans-epicardial uses of mesenchymal stem cells are very safe and feasible. Correction of perfusion defect is very encouraging. Larger studies using higher doses of mesenchymal stem cells may bring about better understanding.
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January 2011

Molecular and cellular characterization of expanded and cryopreserved human limbal epithelial stem cells reveal unique immunological properties.

Exp Eye Res 2011 Jan 18;92(1):47-56. Epub 2010 Nov 18.

Regenerative Medicine Group, Reliance Life Sciences Pvt. Ltd., R-282, TTC Area of MIDC, Thane-Belapur Road, Rabale, Navi Mumbai 400 701, India.

Transplantation of ex vivo expanded autologous limbal stem cells into the diseased eye of patients with limbal stem cell deficiency (LSCD) has been in practice worldwide. However, isolation of limbal tissue from the normal eye of the patient with unilateral LSCD still remains a major concern for the donor. More importantly, autologous cell transplantation is not a viable option for patients with bilateral LSCD. The objective of the current study was to determine the expansion potential of human limbal epithelial stem cells (hLESCs) for their possible use in allo-transplantation. A total of six limbal biopsy samples were cultured and expanded in vitro up to passage level 1 (P-1), at which point the hLESCs were cryopreserved. Semi-quantitative RT-PCR and immunophenotypic analysis revealed that hLESCs obtained before and after cryopreservation retained the expression of major limbal epithelial stem cell markers such as p63, SSEA-4, ABCG2, cytokeratin 19 (CK19), integrin β1 and vimentin. One notable difference was that while P-0 hLESCs expressed HLA-DR mRNA, no HLA-DR gene expression was observed with the expanded and cryopreserved samples. Human LESCs did not express costimulatory proteins CD80 or B7-DC but expressed significant levels of CD86, B7-H1 and HLA-ABC molecules on the cell surface. Treatment of hLESCs with IFN-γ induced the expression of HLA-DR, indoleamine 2,3-dioxygenase (IDO) and HLA-G on these cells. Cultured hLESCs were unable to stimulate allogeneic T cell proliferation in vitro even in the presence of pro-inflammatory cytokine, IFN-γ. These results indicate that cryopreserved hLESCs are non-immunogenic in nature and express negative immunoregulatory molecules which may be critical for their survival in an allogeneic environment.
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http://dx.doi.org/10.1016/j.exer.2010.11.001DOI Listing
January 2011

Derivation, characterization, and gene expression profile of two new human ES cell lines from India.

Stem Cell Res 2010 Nov 1;5(3):173-87. Epub 2010 Aug 1.

Regenerative Medicine, Reliance Life Sciences Pvt Ltd, Dhirubhai Ambani Life Sciences Centre, R-282, TTC Industrial Area of MIDC, Thane Belapur Road, Rabale, Navi Mumbai 400 701, India.

Human embryonic stem cells (hESCs) offer new avenues for studying human development and disease progression in addition to their tremendous potential toward development of cell-replacement therapies for various cellular disorders. We have earlier reported the derivation and characterization of Relicell(®) hES1, the first fully characterized hESC line generated from the Indian subcontinent. Recent studies have demonstrated discrete differences among hESC lines, in terms of both their growth properties and their differentiation propensity. To address some of these issues in the context of hESC research in India, we have recently generated two new hESC lines: Relicell(®) hES2 and Relicell(®)hES3. Both these cell lines were derived using a combinatorial approach of immunosurgery followed by mechanical surgery for inner cell mass isolation. The cell lines exhibit the usual hESC characteristics including their ability to differentiate both in vitro and in vivo to yield the three germinal layers. Whole genome microarray analysis of these cell lines was compared with Relicell(®)hES1 and it showed that approximately 9000 genes were expressed by these lines. As expected the expression pattern of these new cell lines bore close resemblance to that of Relicell(®)hES1. A majority of the pluripotency genes and the genes known to inhibit various differentiation pathways were also expressed by these cell lines. We also observed that each of these cell lines expressed a unique set of genes that are mutually exclusive from each other. These results represent the first detailed characterization of a set of hESC lines originating from India.
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http://dx.doi.org/10.1016/j.scr.2010.07.001DOI Listing
November 2010

Immunologic properties of human dermal fibroblasts.

Hum Immunol 2010 Nov 17;71(11):1089-98. Epub 2010 Sep 17.

Reliance Life Sciences Pvt Ltd., Dhirubhai Ambani Life Sciences Centre, Maharashtra, India.

Human dermal fibroblasts are known not to express human leukocyte antigen (HLA)-DR message or protein in the absence of interferon (IFN)-γ. To use allogeneic dermal fibroblasts for cell therapy, as a revalidation, the cells at passage 12 were analyzed for HLA-DR mRNA and surface protein. Although no significant HLA-DR surface protein was found, HLA-DR mRNA expression was observed, without interferon-γ. At an early passage, although HLA-DR surface protein was not found, prominent expression of HLA-DR mRNA was observed without IFN-γ stimulation, which was not typical of dermal fibroblasts studied so far. Intracytoplasmic HLA-DR protein was also not detected, which suggests that the mRNA was not translated. There was no marked stimulation of T-cell proliferation by the fibroblasts in the absence or presence of IFN-γ. Interestingly, indoleamine dioxygenase, a molecule involved in immunosuppression, was also expressed in dermal fibroblasts in the absence of IFN-γ.
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http://dx.doi.org/10.1016/j.humimm.2010.08.003DOI Listing
November 2010

Intrinsic properties and external factors determine the differentiation bias of human embryonic stem cell lines.

Cell Biol Int 2010 Oct;34(10):1021-31

Regenerative Medicine, Reliance Life Sciences Pvt. Ltd., Thane-Belapur Road, Rabale, Navi Mumbai400 701, India.

A major goal of human embryonic stem cell (hESC) research is to regulate differentiation through external means to generate specific cell types with high purity for regenerative medicine applications. Although all hESC lines express pluripotency-associated genes, their differentiation ability to various lineages differs considerably. We have compared spontaneous differentiation propensity of the two hESC lines, RelicellhES1 and BG01. Spontaneous differentiation of hESC lines grown in different media conditions was followed by differentiation using two methods. Kinetic data generated by real-time gene expression studies for differentiated cell types were analyzed, and confirmed at protein levels. Both cell lines showed upregulation of genes associated with the 3 germ layers, although stark contrast was evident in the magnitude of upregulation of lineage specific genes. A distinct difference was also found in the rate at which the pluripoteny factors, Oct-4 and Nanog, were downregulated during differentiation. Once differentiation was initiated, both Oct-4 and Nanog gene expression was drastically reduced in RelicellhES1, whereas a gradual decrease was observed in BG01. A clear trend is seen in RelicellhES1 to differentiate into neuroectodermal and mesenchymal lineages, whereas BG01 cells are more prone to mesoderm and endoderm development. In addition, suspension versus plated methods of cell culture significantly influenced the outcome of differentiation of certain types of cells. Results obtained by spontaneous differentiation of hESCs were also amplified by induced differentiation. Thus, differential rates of downregulation of pluripotency markers along with culture conditions seem to play an important role in determining the developmental bias of human ES cell lines.
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http://dx.doi.org/10.1042/CBI20100283DOI Listing
October 2010

Derivation, expansion and characterization of clinical grade mesenchymal stem cells from umbilical cord matrix using cord blood serum.

Int J Stem Cells 2010 May;3(2):119-28

Reliance Life Sciences Pvt. Ltd., Dhirubhai Ambani Life Sciences Centre, R-282, TTC Area of MIDC, Thane-Belapur Rd., Rabale, Navi Mumbai - 400701, Maharashtra, India.

Background And Objectives: With increasing use of mesenchymal stem cells (MSCs) in regenerative medicine, there is greater awareness towards the need to have clinical grade products. The bovine media currently used allow good expansion to give large number of MSCs of the right quality. This report brings the significance of using cord blood serum (CBS) in the derivation of MSCs from umbilical cord matrix, to help its clinical applicability.

Methods And Results: MSCs isolated from the cord by explant cultures were expanded and characterized by flow cytometry. Cord blood serum while helping expansion, has the ability to preserve the immunophenotype and differentiation potential of the MSCs derived from the umbilical cords.

Conclusions: Our results suggest that MSCs derived and expanded in cord blood serum are better suited for clinical applications.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4021805PMC
http://dx.doi.org/10.15283/ijsc.2010.3.2.119DOI Listing
May 2010

Umbilical cord matrix derived mesenchymal stem cells can change the cord blood transplant scenario.

Int J Stem Cells 2010 May;3(2):103-18

Regenerative Medicine, Reliance Life Sciences Pvt Ltd, Dhirubhai Ambani Life Sciences Centre, R-282, TTC area of MIDC, Thane Belapur road, Rabale, Navi Mumbai -400701, Maharashtra, India.

Background And Objectives: The field of Umbilical cord blood (UCB) hematopoietic stem cell transplantation has had an amazing run since 1988. UCB is being increasing used in related and unrelated transplant settings. A major hurdle, however, in the use of UCB is its low cell dose, which is largely responsible for an elevated risk of graft failure and significantly delayed neutrophils and platelet engraftment. Strategies to increase CD34(+) HSC/HPC dose are under development as a direct correlation has been shown between these counts and time for engraftment. One strategy includes the ex vivo expansion of UCB derived CD34(+) cells.

Methods And Results: We show that the umbilical cord derived mesenchymal stem cells (UCMSCs) can be used as supporting cells for ex vivo expansion of CD34(+) cells using low concentrations of cytokine cocktail. The UCMSCs release the cytokines required for maintenance and proliferation of CD34(+) cells in the ex vivo culture conditions. More than 25 fold increase in total nucleated cell count (TNC) and more than 20 fold increase in CD34(+) cell count has been obtained using this co-culture system.

Conclusions: UCMSCs from both, autologous and allogeneic origin can be used for expansion of UCB derived CD34(+) cells. The ease of availability and immunoprivileged nature of UCMSCs further holds promise in their use in an allogeneic transplant setting.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4021804PMC
http://dx.doi.org/10.15283/ijsc.2010.3.2.103DOI Listing
May 2010

Immunosuppressive properties of human umbilical cord-derived mesenchymal stem cells: role of B7-H1 and IDO.

Immunol Cell Biol 2010 Nov-Dec;88(8):795-806. Epub 2010 Apr 13.

Regenerative Medicine, Reliance Life Sciences Pvt Ltd, Dhirubhai Ambani Life Sciences Centre, Navi Mumbai, Maharashtra, India.

Umbilical cord is a rich source of mesenchymal stromal or stem cells (MSCs) that can be used for developing allogeneic cell therapy to treat intractable diseases. In this report, we present evidence that umbilical cord-derived MSCs (UCMSCs) possess important immunomodulatory properties that may enable them to survive in an allogeneic environment. UCMSCs do not express human leukocyte antigen (HLA)-DR and co-stimulatory molecules CD80 and CD86 that are required for T-cell activation. More importantly, UCMSCs constitutively express a negative regulator of T-cell activation, B7-H1, and its expression is increased after interferon-γ (IFN-γ) treatment. In addition, IFN-γ treatment induced indoleamine 2,3-dioxygenase (IDO) and HLA-DR expression in UCMSCs. Neither control nor IFN-γ-treated UCMSCs stimulated allogeneic T-cell proliferation, and both cell populations inhibited third-party dendritic cell (DC)-mediated allostimulatory activity. Addition of a B7-H1-specific blocking antibody or an IDO inhibitor, 1 methyl tryptophan (1-MT) abrogated the T-cell immunosuppressive activity of these cells. Furthermore, UCMSCs prevented the differentiation and maturation of peripheral blood monocyte-derived DCs, and augmented the generation of regulatory T cells (Tregs) in culture. The immunosuppressive effects of UCMSCs are largely mediated by cell-to-cell contact, although some inhibitory activity was observed with cell-free supernatant. Our study suggests that these immunomodulatory properties of UCMSCs could potentially improve the outcome of allogeneic stem cell therapy.
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http://dx.doi.org/10.1038/icb.2010.47DOI Listing
June 2011

Comparison of proliferative and multilineage differentiation potentials of cord matrix, cord blood, and bone marrow mesenchymal stem cells.

Asian J Transfus Sci 2010 Jan;4(1):14-24

Regenerative Medicine Group, Reliance Life Sciences Pvt. Ltd., Navi Mumbai, India.

Background: Hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) are the two widely studied and characterized adult stem cells. Thus far, MSCs were obtained from the bone marrow, which is a painful procedure. Therefore, MSCs from less common sources like cord blood, adipose tissue, tooth pulp, and so on, have been the subject of research. The purpose of this study is to explore the possibility of finding MSCs from a less controversial, easy, and abundant source, such as the umbilical cord, for potential regenerative medicine applications.

Study Design And Methods: Five bone marrow samples (BM), seventy cord blood units (CB), and four umbilical cord matrix (CM) samples have been used for the study. Expanded MSCs were checked for biomarker expression by flow cytometry and were also checked for their differentiation to mesodermal and ectodermal lineages.

Results: MSCs could be isolated from 100% BM and CM samples, as compared to only 6% of CB samples. The fold expansion of the mesenchymal stem cells observed in CB (CB-MSCs) was distinctly higher as compared to BM (BM-MSCs) and CM (CM-MSCs). MSCs isolated from all the three sources expressed a characteristic mesenchymal phenotype of CD45 - /vWF - /CD14 - /CD31 - /CD73 + /CD105 + /SSEA4 + /CD29 + /CD44 + /HLAABC +, whereas, the HLA DR was conspicuously absent in CM-MSCs and CB-MSCs. Although osteogenic, chondrogenic, and neural differentiation was observed in MSCs from all sources, adipogenic differentiation was observed only in BM-MSCs.

Conclusion: CM-MSCs are a dependable source of an unlimited number of MSCs for autologous and allogenic use in regenerative medicine.
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http://dx.doi.org/10.4103/0973-6247.59386DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2847339PMC
January 2010

India's first public cord blood repository - looking back and moving forward.

Indian J Hematol Blood Transfus 2009 Sep 12;25(3):111-7. Epub 2009 Nov 12.

Reliance Life Sciences Pvt. Ltd., R-282, DALSC, Thane - Belapur Road, Rabale, Navi Mumbai, India.

Umbilical cord blood is an established source of stem cells useful for hematopoetic reconstitution. The first clinical transplantation in France by Eliane Gluckman in 1988 using HLA matched umbilical cord blood from a sibling on a 6-year-old boy with Fanconi's anemia is an example of a successful transplantation. So far, more than 8,000 patients worldwide have been treated for malignant and inherent blood disorders [1, 2]. Our cord blood repository (CBR) was established as the part of the Life Sciences initiative, almost 7 years ago. The cord blood program consisted of developing a good network of obstetricians and social workers, develop manpower in various aspects of the banking activity, develop methods of process and analysis and above all, increase the level of awareness among the medical, paramedical fraternity and the general public on the cord blood program. The present paper gives a detailed account of our experience as we set up the repository.
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http://dx.doi.org/10.1007/s12288-009-0023-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3453424PMC
September 2009

Clinical grade mesenchymal stem cells transdifferentiated under xenofree conditions alleviates motor deficiencies in a rat model of Parkinson's disease.

Cell Biol Int 2009 Aug 22;33(8):830-8. Epub 2009 May 22.

Regenerative Medicine, Haematopoietic Stem Cell Group, Dhirubhai Ambani Life Sciences Centre, R-282 TTC Area of MIDC, Thane Belapur Road, Rabale, Navi Mumbai 400701, India.

Unlabelled: Bone marrow derived mesenchymal stem cells (BMMSCs) is a valid, definitive candidate for repair of damaged tissues in degenerative disorders in general and neurological diseases in particular. We have standardized the processing conditions for proliferation of BMMSCs using xenofree medium and checked their in vitro and in vivo neurogenic potential.

Method: The proliferative potential of BMMSCs was analyzed using xenofree media and functionality checked by transplantation into Parkinson's disease (PD) animal models. In vitro neuronal differentiation was investigated by neuronal induction media supplemented with growth factors. Differentiated cells were characterized at cellular and molecular levels. In vitro functionality estimated by dopamine secretion.

Results: A pure population of BMMSCs showing an 8-10 fold expansion was obtained using xenofree media. On differentiation to neuronal lineage, they exhibited neuronal morphology. Detectable levels of dopamine (1.93 ng/ml) were secreted into the culture media of differentiated cells. There was a significant behavioural improvement in PD models 3 months post transplantation.

Conclusion: Our study demonstrates that BMMSCs can be transdifferentiated efficiently into functional dopaminergic neurons both in vitro and in vivo. This holds immense clinical potential as a replacement therapy for PD and other neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.cellbi.2009.05.002DOI Listing
August 2009