Publications by authors named "Sandeep Kumar Vishwakarma"

26 Publications

  • Page 1 of 1

Fabrication of Decellularized Amnion and Chorion Scaffolds to Develop Bioengineered Cell-Laden Constructs.

Cell Mol Bioeng 2022 Feb 24;15(1):137-150. Epub 2021 Sep 24.

Central Laboratory for Stem Cell Research & Translational Medicine, Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Kanchanbagh, Hyderabad, Telangana 500058 India.

Introduction: Human mesenchymal stem cells (hMSCs) holds great promise for managing several clinical conditions. However, the low engraftment efficiency and obscurity to harvest these cells without compromising the cellular viability, structural and functional properties from the culture niche still remain major obstacles for preparing intact regenerative constructs. Although few studies have demonstrate different methods for generating cell-liberated amniotic scaffolds, a common method for producing completely cell-liberated amnion (D-HAM) and chorion (D-HCM) scaffolds and their cytocompatibility with hMSCs yet to be demonstrated.

Methods: A common process was developed for preparing D-HAM and D-HCM scaffolds for assessing hMSCs engraftment efficiency, proliferation and molecular shifts to generate cell-laden biological discs. The structural and functional integrity of D-HAM and D-HCM was evaluated using different parameters. The compatibility and proliferation efficiency of hMSCs with D-HAM and D-HCM was evaluated.

Results: Histological analysis revealed completely nucleic acid-free D-HAM and D-HCM scaffolds with intact extracellular matrix, mechanical and biological properties almost similar to the native membranes. Human MSCs were able to adhere and engraft on D-HCM better than D-HAM and expanded faster. Ultrastructural observations, crystal violet staining and expression studies showed better structural and functional integrity of hMSCs on D-HCM than D-HAM and control conditions.

Conclusion: A common, simple and reliable process of decellularization can generate large number of cell-liberated amniotic scaffolds in lesser time. D-HCM has better efficiency for hMSCs engraftment and proliferation and can be utilized for preparing suitable cell-laden constructs for tissue engineering applications.
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http://dx.doi.org/10.1007/s12195-021-00707-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8761215PMC
February 2022

Biofabrication of allogenic bone grafts using cellularized amniotic scaffolds for application in efficient bone healing.

Tissue Cell 2021 Dec 25;73:101631. Epub 2021 Aug 25.

Central Laboratory for Stem Cell Research & Translational Medicine, Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Kanchanbagh, Hyderabad, 500058, Telangana, India. Electronic address:

Introduction: The reconstruction/regeneration of human bone injuries/defects represents a crucial challenge due to the lack of suitable bio/immune compatible and implantable biological grafts. The available strategies represent implications of several types of grafting materials in the form of metals, synthetic, and various kinds of biological scaffolds; however, the lack of appropriate biological components required for activating and enhancing repair mechanisms at the lesion-site limits their wider applicability.

Methods: In this study, a unique approach for generating human osteogenic implantable grafts was developed using biofabrication technology. Using a gradient change of detergents and continuous agitation, developed a unique technique to generate completely cell-free amnion and chorion scaffolds. The absence of cellular components and integrity of biological and mechanical cues within decellularized human amnion (D-HAM) and chorion (D-HCM) were evaluated and compared with fresh membranes. Allogenic bone grafts were prepared through induction of human mesenchymal stem cells (hMSCs) into osteogenic cells on D-HAM and D-HCM and evaluated for their comparative behavior at the cellular, histological and molecular levels.

Results: The common decellularization process resulted in an efficient way to generate D-HAM and D-HCM while retaining their intact gross-anatomical architecture, surface morphology, extracellular matrix components, and mechanical properties. Both these scaffolds supported better growth of human umbilical cord blood derived MSCs as well as osteogenic differentiation. Comparative investigation revealed better growth rate and differentiation on D-HCM compared to D-HAM and control conditions.

Conclusion: D-HCM could be used as a better choice for producing suitable allogenic bone grafts for efficient bone healing applications.
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http://dx.doi.org/10.1016/j.tice.2021.101631DOI Listing
December 2021

Status of Vitamin D Receptor Gene Polymorphism and 25-Hydroxy Vitamin D Deficiency with Essential Hypertension.

Indian J Clin Biochem 2021 Jun 15:1-7. Epub 2021 Jun 15.

Central Laboratory for Stem Cell Research and Translational Medicine, Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Kanchanbagh, Hyderabad, Telangana 500058 India.

Essential hypertension (EH) is a multifactorial and complex disease with high rate of incidence and associated co-morbidities. Previous studies do not provide unanimous results for the risk of hypertension and association with Fok I genotype frequency and serum vitamin D levels. Hence, this study was undertaken to determine the status of Fok I vitamin D receptor (VDR) gene polymorphism along with vitamin D levels and blood pressure in patients with EH. Four hundred (200 controls and 200 cases of essential hypertension) participants from general Indian population were enrolled in this study. Peripheral blood samples were collected for genotyping Fok I-VDR gene polymorphism using PCR-RFLP method whereas 25-OH vitamin D levels in serum were quantified using high performance liquid chromatography (HPLC). Significantly reduced 25-OH vitamin D levels were observed in patients with EH (24.04 ± 8.62 vs 50.46 ± 15.46) compared to control subjects ( = 0.0001). Homozygous recessive genotype 'ff' frequency was increased by 8.06 fold (CI: 3.71-17.47,  = 0.0001) in patients with EH compared to dominant 'FF' genotype frequency. In conclusion, recessive 'ff' genotype frequency correlates with reduced serum vitamin D levels and results in significantly increased systolic and diastolic blood pressures leading to predisposition of EH.
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http://dx.doi.org/10.1007/s12291-021-00984-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203720PMC
June 2021

Biofabrication of cell-laden allografts of goat urinary bladder scaffold for organ reconstruction/regeneration.

Tissue Cell 2020 Dec 28;67:101443. Epub 2020 Sep 28.

Central Laboratory for Stem Cell Research and Translational Medicine, Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Kanchanbagh, Hyderabad 500058, Telangana, India. Electronic address:

Introduction: Bladder dysfunction has been considered as one of the most critical health conditions with no proper treatment. Current therapeutic approaches including enterocystoplasty have several limitations. Hence, biofabrication of cell-laden biological allografts using decellularized Goat urinary bladder scaffolds for organ reconstruction/regeneration was major objective of this study.

Materials And Methods: An efficient method for decellularization of Goat urinary bladder (N = 3) was developed by perfusion of gradient change of detergents through ureter. The retention of organ architecture, extracellular matrix composition, mechanical properties and removal of cellular components was characterized using histological, cellular and molecular analysis. Further, mesenchymal stem cells (MSCs) from human umbilical cord blood (UCB) were used for preparing biological construct of decellularized urinary bladder (DUB) scaffolds to augment the urinary bladder reconstruction/regeneration.

Results: The decellularization method adopted in this study generated completely DUB scaffolds within 10 h at 100 mm Hg pressure and constant flow rate of 1 mL/min. The DUB scaffold retains organ architecture, ECM composition, and mechanical strength. No significant amount of residual nucleic acid was observed post-decellularization. Furthermore, MSCs derived from human UCB engrafted and proliferated well on DUB scaffolds in highly aligned manner under xeno-free condition.

Conclusion: Biofabricated humanized urinary bladder constructs provides xeno-free allografts for future application in augmenting urinary bladder reconstruction/regeneration with further development.
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http://dx.doi.org/10.1016/j.tice.2020.101443DOI Listing
December 2020

Osteo/odontogenic Differentiation of Human Mesenchymal Stem Cells with Platelet-rich Plasma and Mineral Trioxide Aggregate.

J Contemp Dent Pract 2019 Oct 1;20(10):1171-1178. Epub 2019 Oct 1.

Centre for Liver Research and Diagnostics (CLRD), Central Laboratory for Stem Cell Research and Translational Medicine, Deccan College of Medical Sciences, Hyderabad, Telangana, India.

Aim: Aim of the study was to investigate the effect of PRP and MTA individually and combined on human bone marrow mesenchymal stem cells' (MSCs) proliferation and osteo/odontogenic differentiation potential.

Materials And Methods: MSCs were cultured with MTA, 5% PRP, 10% PRP, MTA with 5%PRP, and MTA with 10% PRP. Fetal calf serum (FCS) was used as control. Cell viability and proliferative efficiency were tested with cell adhesion and MTT assay. Osteo/odontogenic differentiation was assessed and quantified with alizarin red staining.

Results: MTA alone, MTA with 5% PRP, and MTA with 10% PRP showed significantly high proliferation at day 7 and 14 when compared to the control group. Enhanced differentiation and the highest calcium deposition was observed in MTA with the 10% PRP group.

Conclusion: Within limitations of the environment, results imply an increased proliferation and induction of MSCs into osteo/odontogenic differentiation by the combination rather than a mere sealing of PRP by MTA.

Clinical Significance: PRP and MTA have the potential for true regeneration of the pulp tissue. Moreover, the combination of PRP and MTA can be utilized to expand the MSCs to generate adequate numbers for clinical applications, without xenogenic contamination. How to cite this article: Vanka A, Vishwakarma SK, Bhat MK, Osteo/odontogenic Differentiation of Human Mesenchymal Stem Cells with Platelet-rich Plasma and Mineral Trioxide Aggregate. J Contemp Dent Pract 2019;20(10):1171-1178.
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October 2019

Engineering bio-mimetic humanized neurological constructs using acellularized scaffolds of cryopreserved meningeal tissues.

Mater Sci Eng C Mater Biol Appl 2019 Sep 12;102:34-44. Epub 2019 Apr 12.

Central Laboratory for Stem Cell Research and Translational Medicine, Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Kanchanbagh, Hyderabad 500058, Telangana, India; Dr Habeebullah Life Sciences, Attapur, Hyderabad, Telangana, India. Electronic address:

Spinal cord injury (SCI) is one of the most precarious conditions which have been one of the major reasons for continuous increasing mortality rate of SCI patients. Currently, there is no effective treatment modality for SCI patients posing major threat to the scientific and medical community. The available strategies don't mimic with the natural processes of nervous tissues repair/regeneration and majority of the approaches may induce the additional fibrotic or immunological response at the injury site and are not readily available on demand. To overcome these hurdles, we have developed a ready to use bioengineered human functional neurological construct (BHNC) for regenerative applications in SCI defects. We used cryopreserved meningeal tissues (CMT) for bioengineering these neurological constructs using acellularization and repopulation technology. The technology adopted herein generates intact neurological scaffolds from CMT and retains several crucial structural, biochemical and mechanical cues to enhance the regenerative mechanisms. The neurogenic differentiation on CMT scaffolds was almost similar to the freshly prepared meningeal scaffolds and mimics with the natural nervous tissue developmental mechanisms which offer intact 3D-microarchitecture and hospitable microenvironment enriched with several crucial neurotrophins for long-term cell survival and function. Functional assessment of developed BHNC showed highly increased positive staining for pre-synaptic granules of Synapsis-1 along with MAP-2 antibody with punctuate distribution in axonal regions of the neuronal cells which was well supported by the gene expression analysis of functional transcripts. Given the significant improvement in the field may enable to generate more such ready to use functional BHNC for wider applicability in SCI repair/regeneration.
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http://dx.doi.org/10.1016/j.msec.2019.04.028DOI Listing
September 2019

Intraperitoneal transplantation of bioengineered humanized liver grafts supports failing liver in acute condition.

Mater Sci Eng C Mater Biol Appl 2019 May 14;98:861-873. Epub 2019 Jan 14.

Central Laboratory for Stem Cell Research and Translational Medicine, Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Kanchanbagh, Hyderabad 500058, Telangana, India; Dr. Habeebullah Life Sciences, Attapur, Hyderabad 500048, Telangana, India. Electronic address:

Acute liver failure (ALF) is one of the most devastating fatal conditions which have posed crucial challenges to the clinicians and researchers for identifying permanent cure. Currently liver transplantation has been considered as the only managerial option. However it's wider applicability has been limited owing to non-availability of quality donor organs, cost-intensiveness, surgical hitches, life-long use of immunosuppressive drugs and long-term complications. Since last decades, several liver support systems have been developed for the management of failing liver in acute condition. However, the major limitation has been the lack of natural biological support and long-term survival of the grafts post-transplantation. Repopulation of decellularized xenogeneic organs is one of the emerging technologies for development of humanized neo-organs for demanding regenerative application. However, the earlier reported studies do not fulfil the insistence to provide immunologically tolerable humanized liver grafts for clinical applications. Here we demonstrate an efficient approach to generate transplantable humanized liver grafts which provides long-term support to the failing liver in Acute Liver Failure (ALF) animal models. These bioengineered humanized liver tissue grafts expresses several liver specific transcripts and performed crucial synthetic (albumin production) and detoxification (urea synthesis) functions at comparative level to normal liver. Intraperitoneal transplantation of these humanized liver grafts offered favourable microenvironment to exchange toxic substances across the barrier during ALF condition and provided long-term survival and function of the graft. In summary, the results of present study provide a first proof of concept in pre-clinical ALF animal model for the applicability of these bioengineered humanized livers in the management of failing liver on demand and may be considered as potential bridge to liver transplantation.
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http://dx.doi.org/10.1016/j.msec.2019.01.045DOI Listing
May 2019

Activation of integrated stress response pathway regulates IL-1β production through posttranscriptional and translational reprogramming in macrophages.

Eur J Immunol 2019 02 4;49(2):277-289. Epub 2019 Jan 4.

Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad, India.

Immune cells sense and programme its cellular machinery appropriately to the environmental changes through the activation of cytoprotective adaptive pathway so-called the "integrated stress response (ISR)". However, the mechanisms implicated in ISR-induced protective responses are poorly understood. Here, we show that ISR activation by arsenite (Ar) results in suppression of IL-1β production in macrophages and inhibition of DSS-induced colitis in a murine model through a novel posttranscriptional and translation regulatory (PTR) mechanism. Ar triggers PTR events through eIF2α-phosphorylation, which results in the attenuation of active polysome formation leading to the accumulation of translationally stalled IL-1β mRNAs. Translationally stalled IL-1β mRNAs recruit RNA-binding proteins (TIA-1/TIAR), resulting in the formation of RBP-RNA complexes known as stress granules (SGs). The SGs bound IL-1β mRNAs might undergo degradation through induction of autophagy. Also, we show that Ar posttranslationally impairs processing and secretion of IL-1β by diminishing inflammasome activation. Altogether, this study unveils a novel mechanism of IL-1β regulation and further suggests that pharmacological activation of cytoprotective ISR pathway might provide an effective therapeutic intervention against inflammatory diseases.
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http://dx.doi.org/10.1002/eji.201847513DOI Listing
February 2019

Bioengineered functional humanized livers: An emerging supportive modality to bridge the gap of organ transplantation for management of end-stage liver diseases.

World J Hepatol 2018 Nov;10(11):822-836

Central Laboratory for Stem Cell Research and Translational Medicine, Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Kanchanbagh, Hyderabad 500058, Telangana, India.

End stage liver diseases (ESLD) represent a major, neglected global public health crisis which requires an urgent action towards finding a proper cure. Orthotropic liver transplantation has been the only definitive treatment modality for ESLD. However, shortage of donor organs, timely unavailability, post-surgery related complications and financial burden on the patients limits the number of patients receiving the transplants. Since last two decades cell-based therapies have revolutionized the field of organ/tissue regeneration. However providing an alternative organ source to address the donor liver shortage still poses potential challenges. The developments made in this direction provide useful futuristic approaches, which could be translated into pre-clinical and clinical settings targeting appropriate applications in specific disease conditions. Earlier studies have demonstrated the applicability of this particular approach to generate functional organ in rodent system by connecting them with portal and hepatic circulatory networks. However, such strategy requires very high level of surgical expertise and also poses the technical and financial questions towards its future applicability. Hence, alternative sites for generating secondary organs are being tested in several types of disease conditions. Among different sites, omentum has been proved to be more appropriate site for implanting several kinds of functional tissue constructs without eliciting much immunological response. Hence, omentum may be considered as better site for transplanting humanized bioengineered generated livers, thereby creating a secondary organ at intra-omental site. However, the expertise for generating such bioengineered organs are limited and only very few centres are involved for investigating the potential use of such implants in clinical practice due to gap between the clinical transplant surgeons and basic scientists working on the concept evolution. Herein we discuss the recent advances and challenges to create functional secondary organs through intra-omental transplantation of generated bioengineered humanized livers and their further application in the management of ESLD as a supportive bridge for organ transplantation.
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http://dx.doi.org/10.4254/wjh.v10.i11.822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280164PMC
November 2018

Bioengineering Human Neurological Constructs Using Decellularized Meningeal Scaffolds for Application in Spinal Cord Injury.

Front Bioeng Biotechnol 2018 1;6:150. Epub 2018 Nov 1.

Central Laboratory for Stem Cell Research and Translational Medicine, CLRD, Deccan College of Medical Sciences, Kanchanbagh, Hyderabad, India.

Spinal cord injury (SCI) is one of the most devastating conditions echoes with inflammation, enhanced fibrosis and larger axonal gaps due to destruction of neurological cells which has caused continuous increasing mortality rate of SCI patients due to absence of suitable treatment modalities. The restoration of structural and functional aspect of damaged neurological tissues at the lesion site in spinal cord has been challenging. Recent developments have showed tremendous potential of neural stem cell-based strategies to form a neuronal relay circuit across the injury gap which facilitates some levels of improvement in SCI condition. However, to provide better therapeutic responses, critical mass of grafted cells must survive for long-term and differentiate into neuronal cells with well-developed axonal networks. Hence, development of tissue specific biological neuronal constructs is highly desirable to provide mechanical and biological support for long-term survival and function of neurological cells within natural biological niche. In this study, we report development of a tissue specific neuronal constructs by culturing human neural precursor cells on decellularized meningeal scaffolds to provide suitable biological neuronal construct which can be used to support mechanical, structural and functional aspect of damaged spinal cord tissues. This particular tissue specific biological construct is immunologically tolerable and provides precisely orchestral three-dimensional platform to choreograph the long-distance axonal guidance and more organized neuronal cell growth. It passes sufficient mechanical and biological properties enriched with several crucial neurotrophins required for long-term survival and function of neurological cells which is required to form proper axonal bridge to regenerate the damaged axonal connectomes at lesion-site in SCI.
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http://dx.doi.org/10.3389/fbioe.2018.00150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221909PMC
November 2018

Transcriptome meta-analysis identifies immune signature comprising of RNA binding proteins in ulcerative colitis patients.

Cell Immunol 2018 12 21;334:42-48. Epub 2018 Sep 21.

Central Laboratory for Stem Cell Research and Translational Medicine, Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Kanchanbagh, Hyderabad-500058, Telangana, India. Electronic address:

Ulcerative colitis (UC) is a persistent inflammatory illness, which is clinically categorised as Inflammatory bowel disease (IBD), affecting millions of people worldwide. The precise cause behind the pathology of the disease remains unknown. However, the involvement of multiple factors including genetic predisposition, immunological deregulations, microbiota imbalance, and environmental triggers has been suggested. Amongst all these factors, the over-active immunological response reported in UC patients seems to be a promising target for therapy. Moreover, identification of gene signatures associated with disease onset and progression would help in better understanding of the molecular mechanisms involved in the disease pathogenesis. Here, we have conducted meta-analysis of gene expression profiles of UC patient microarray datasets accessible in public databases and further validated the in-silico findings in UC patients' blood samples. Our study reveals that UC pathogenesis perturbs expression of several inflammatory genes. In addition, we report a novel gene signature comprising of TIA1 (T cell restricted intracellular antigen) and TIAR (TIA1 related protein; also known as TIAL1), which were found to be significantly downregulated in UC patients. TIA1 and TIAR are RNA-binding proteins (RBPs), which function as a translational represser by binding to ARE sequences in the 3' UTR of mRNAs encoding inflammatory mediators including cytokines. Our findings demonstrate that deletion of TIAR using gene specific siRNAs in-vitro results in enhanced production of inflammatory cytokine IL-1β. In conclusion, the findings of this study reveal that down regulation of TIA1/TIAR genes could be responsible for UC associated inflammation. This study highlights the usefulness of the meta-analysis approach in the identification of unique gene signatures that might deliver mechanistic insights into UC pathogenesis and possibly assist in discovery of prognostic markers and therapeutic interventions.
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http://dx.doi.org/10.1016/j.cellimm.2018.09.003DOI Listing
December 2018

Molecular dynamics of pancreatic transcription factors in bioengineered humanized insulin producing neoorgan.

Gene 2018 Oct 3;675:165-175. Epub 2018 Jul 3.

Central Laboratory for Stem Cell Research & Translational Medicine, Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Kanchanbagh, Hyderabad 500058, Telangana, India; Dr. Habeebullah Life Sciences, Attapur, Hyderabad 500030, Telangana, India. Electronic address:

Background: The present study has been aimed to identify molecular dynamics of pancreatic transcription factors (pTFs) during events of directed trans-differentiation of human hepatic progenitor cells (hHPCs) into insulin producing cells (InPCs) within bioengineered humanized neoorgan. The study demonstrates applicability of acellularized whole splenic scaffold (ASOS) to generate insulin producing humanized transplantable neoorgan through activation of pancreatic transcription factors.

Methods: An efficient acellularization process was developed for xenogeneic rat spleen using change in different gradients of reagents perfusion through splenic artery for varying time points. The acellularized xenogeneic spleen scaffold was characterized thoroughly for preservation of extra-cellular matrix and retention of organ specific vasculature and mechanical properties. Further scaffolds were sterilized and repopulated with hHPCs which were triggered using a stage wise induction with growth factors and hyperglycemic challenge for trans-differentiation into InPCs. Dynamics of pTFs alone or simultaneously during induction process was identified using gene expression analysis and immunological staining.

Results: The cells within the engineered neoorgan respond to growth factors and extrinsic hyperglycemic challenge and generate large number of InPCs under controlled dynamic regulation of pTFs. Highly controlled regulation of pTFs generates higher percentage of Nkx-6.1+/C-peptide+ cells within the engineered splenic scaffolds. Generation of high percentage of insulin and C-peptide positive cells in three-dimensional organ architecture responded better to hyperglycemic stimuli and produced higher quantity of insulin than 2D-culture system.

Conclusion: The present study provides a novel platform for designing effective regenerative strategies using whole organ scaffolds to control hyperglycemia under tight regulation of pTFs using humanized neoorgan system.
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http://dx.doi.org/10.1016/j.gene.2018.07.006DOI Listing
October 2018

Protective Role of Hypothermia Against Heat Stress in Differentiated and Undifferentiated Human Neural Precursor Cells: A Differential Approach for the Treatment of Traumatic Brain Injury.

Basic Clin Neurosci 2017 Nov-Dec;8(6):453-466

Central Laboratory for Stem Cell Research and Translational Medicine, Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Hyderabad, India.

Introduction: The present study aimed to explore protective mechanisms of hypothermia against mild cold and heat stress on highly proliferative homogeneous human Neural Precursor Cells (NPCs) derived from Subventricular Zone (SVZ) of human fetal brain.

Methods: CD133+ve enriched undifferentiated and differentiated human NPCs were exposed to heat stress at 42°C. Then, Western-blot quantification was performed using Hsp-70 (70 kilodalton heat shock proteins) recombinant protein. Finally, changes in pluripotency and Hsp-70 expression were measured using immunofluorescence staining and RT-qPCR (Quantitative reverse transcription PCR) analysis, respectively.

Results: Heat stress resulted in abnormal neurospheres development. The apoptosis rate was enhanced during long-term in vitro culture of neurospheres. Neurogenic differentiation reduced and showed aberrent phenotypes during heat stress. After hypothermia treatment significant improvement in neurospheres and neuronal cell morphology was observed.

Conclusion: Mild-hypothermia treatment induces attenuated heat shock response against heat stress resulting in induced HSP-70 expression that significantly improves structure and function of both undifferentiated human NPCs and differentiated neurons.
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http://dx.doi.org/10.29252/NIRP.BCN.8.6.453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010658PMC
June 2018

In vitro hemocompatability evaluation of gold nanoparticles capped with Lactobacillus plantarum derived lipase1.

Clin Hemorheol Microcirc 2018 ;69(1-2):197-205

Department of Biological Sciences, BITS Pilani, Hyderabad Campus, Jawahar Nagar, Shameerpet Mandal, Hyderabad, Telangana, India.

Background: Gold nanoparticles (GNPs) are key diagnostic and therapeutic agents in biomedical sciences. Several studies have been carried out in different therapeutic areas such as in cancer treatment, antibacterial topical agents, imaging agents etc. There is a necessity to evaluate the gold nanoparticles cytotoxicity at all fronts. Since blood is the first point of contact in any therapy, it is required to have a thorough in vitro investigation of gold nanoparticles to avoid any adverse effects.

Objective: The objective of the current study is to evaluate the effect of gold nanoparticles capped with lipase on blood clotting factors, platelets, coagulation time and blood clotting strength.

Methods: Whole blood samples were drawn from healthy volunteers. Plasma and plasma with platelets were isolated from the blood and all the samples were treated with lipase capped gold nanoparticles, except control. Plasma fibrinogen formed in the blood coagulation process after contacting with nanoparticles was quantitatively evaluated. In addition, platelet aggregation, blood clotting kinetics, strength of the blood clot and time were evaluated post nanoparticle treatment.

Results: The work primarily explores the effect of GNPs on blood with changing concentrations of lipase capping. Plasma fibrinogen levels of plasma samples were found to be moderately elevated, however, there is no significant effect on blood clotting kinetics, strength, and platelet aggregation. Also, the study showed that lipase capped GNPs did not result in aggregation upon interaction with plasma components and remained stable for 1 hour after incubation.

Conclusions: Our study revealed that lipase capped GNPs synthesized using NaBH4 approach were stable and hemocompatible. There is an increase in fibrinogen levels after the exposure to nanoparticles, an observation which is consistent with other studies. However, the functional consequences of such increase are unknown. The results of no significant platelet aggregation, change in blood clotting time, kinetics, and clot strength revealed the non-toxic effect of lipase capped GNPs towards blood components, which is essential for any in vivo applications.
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http://dx.doi.org/10.3233/CH-189117DOI Listing
June 2018

Role of drug transporters and heat shock proteins during ethanol exposure to human neural precursor cells and its lineages.

Tissue Cell 2018 Apr 7;51:14-23. Epub 2018 Feb 7.

Central Laboratory for Stem Cell Research & Translational Medicine, Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Kanchanbagh, Hyderabad, 500058, Telangana, India. Electronic address:

Introduction: Ethanol exposure to developing brain may alter the growth and differentiation of neurological cells resulting in unfavorable pathologies. Earlier studies have provided very limited mechanistic insights of cellular and molecular mechanisms which do not mimic with human situation due to varying cell types and poses potential challenges for investigation. Therefore, the present study was undertaken to evaluate the role of ABC transporters and heat shock proteins mediated response in human neural precursor cells (NPCs) and its lineages during proliferation and lineage differentiation against ethanol exposure.

Methods: Effect of ethanol exposure was examined for neuronal cell survival and variation in cellular phenotype during neurospheres development and lineage differentiation. Generation of reactive oxygen species, and variation in cell cycle was identified along with transcriptional profiling for pluripotent markers (Nestin, NCAM, Sox-2, and Notch-2), drug transporters (ABCB1 and ABCG2) and stress protein (HSP70) during ethanol exposure.

Results: ABC transporters as well as HSP70 mRNA expression was higher during proliferation as compared to differentiation with chronic ethanol (1 M) exposure (p < 0.01). Ethanol exposure resulted in higher variability in size and shape of developing neurospheres and decreased ability to form new neurosphere colonies. Significant changes were observed in dendrite development due to late ethanol exposure (p < 0.0001).

Conclusion: The present study demonstrated significant role of ABC transporters and HSP70 proteins in providing defense against ethanol-induced damage in human neurological cells. However, the over-expression of ABC transporter and HSP-70 proteins during such pathological conditions do not provide complete defense and additional strategies are required to repair the damage.
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http://dx.doi.org/10.1016/j.tice.2018.02.001DOI Listing
April 2018

Bioengineered humanized livers as better three-dimensional drug testing model system.

World J Hepatol 2018 Jan;10(1):22-33

Central Laboratory for Stem Cell Research and Translational Medicine, Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Hyderabad 500058, Telangana, India.

Aim: To develop appropriate humanized three-dimensional model system for drug testing.

Methods: Bioengineered humanized livers were developed in this study using human hepatic stem cells repopulation within the acellularized liver scaffolds which mimics with the natural organ anatomy and physiology. Six cytochrome P-450 probes were used to enable efficient identification of drug metabolism in bioengineered humanized livers. The drug metabolism study in bioengineered livers was evaluated to identify the absorption, distribution, metabolism, excretion and toxicity responses.

Results: The bioengineered humanized livers showed cellular and molecular characteristics of human livers. The bioengineered liver showed three-dimensional natural architecture with intact vasculature and extra-cellular matrix. Human hepatic cells were engrafted similar to the human liver. Drug metabolism studies provided a suitable platform alternative to available and models for identifying cellular and molecular dynamics of pharmacological drugs.

Conclusion: The present study paves a way towards the development of suitable humanized preclinical model systems for pharmacological testing. This approach may reduce the cost and time duration of preclinical drug testing and further overcomes on the anatomical and physiological variations in xenogeneic systems.
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http://dx.doi.org/10.4254/wjh.v10.i1.22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787681PMC
January 2018

Enhanced neuroprotective effect of mild-hypothermia with VPA against ethanol-mediated neuronal injury.

Tissue Cell 2017 Dec 14;49(6):638-647. Epub 2017 Sep 14.

Central Laboratory for Stem Cell Research and Translational Medicine, CLRD, Deccan College of Medical Sciences, Hyderabad 500058, Telangana, India. Electronic address:

Introduction: Progress in understanding pathophysiological mechanisms and the development of targeted regenerative strategies have been hampered by the lack of predictive disease models, specifically for the conditions to which affected cell types are inaccessible. The present study has aimed to unearth the role of valproic acid (VPA) and mild hypothermia (MH) as promising strategy to enhance the neuroprotective mechanisms in undifferentiated and differentiated human neural precursor cells (hNPCs) against ethanol-induced damage.

Methods: 5mM VPA alone or in combination with MH (33°C) was used to prevent the damage in proliferating and differentiating hNPCs. CD133+ve enriched hNPCs were cultured in vitro and exposed to 1M chronic ethanol concentration for 72h and followed by VPA and MH treatment for 24h. Morphometric analysis was performed to identify changes in neurospheres development and neuronal cell phenotypes. Flow cytometry and RT-qPCR analysis was performed to investigate alterations in key molecular pathways involved in cell survival and signaling.

Results: Combination of VPA with MH displayed higher proportion of neuronal cell viability as compared to single treatment. Combination treatment was most effective in reducing apoptosis and reactive oxygen species levels in both the undifferentiated and differentiated hNPCs. VPA with MH significantly improved neuronal cell phenotype, active chromatin modeling, chaperon and multi-drug resistant pumps activity and expression of neuronal signaling molecules.

Conclusion: The study provided an efficient and disease specific in vitro model and demonstrated that combined treatment with VPA and MH activates several neuroprotective mechanisms and provides enhanced protection against ethanol-induced damage in cultured undifferentiated and differentiated hNPCs.
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http://dx.doi.org/10.1016/j.tice.2017.09.004DOI Listing
December 2017

Use of Biocompatible Sorafenib-gold Nanoconjugates for Reversal of Drug Resistance in Human Hepatoblatoma Cells.

Sci Rep 2017 08 17;7(1):8539. Epub 2017 Aug 17.

Clinical Research Facility, Medical Biotechnology Complex, CSIR-Centre for Cellular and Molecular Biology, Uppal Road, Habsiguda, Hyderabad, 500007, Telangana, India.

The present study identifies the potential of highly biocompatible SF-GNP nano-conjugate to enhance the chemotherapeutic response to combat drug resistance in cancer cells. We developed a stable colloidal suspension of sorafenib-gold nanoconjugate (SF-GNP) of <10 nm size in aqueous medium for reverting the cancer drug resistance in SF-resistant HepG2 cells in a 3D ex-vivo model system. In-vivo biocompatibility assay of SF-GNPs showed absence of systemic toxicological effects including hematological, biochemical and histological parameters. More importantly, the histopathological analysis of vital organs such as liver, brain, lung, kidney and heart showed very least or no sign of inflammation, cell infiltration, necrosis, tissue disorganization or fibrotic reactions after intra-peritoneal administration of SF-GNP nanoconjugates in animals. However, SF-GNP nanoconjugates significantly reduced (>80%) the percentage cell survival and the size and number of SF resistant solid tumor colonies of HepG2 cells in 3D model system. The exposure of SF-GNP nanoconjugate to SF resistant HepG2 cell colonies also provided evidence for anti-proliferative effect and reversal of drug resistance by elucidating the molecular regulatory mechanisms of extracellular matrix factor (CD147), tumor growth factor (TGF-β), hepatoma upregulated protein (hURP) and drug transporter (ABCG-2).
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http://dx.doi.org/10.1038/s41598-017-08878-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5561190PMC
August 2017

Protective Effects of Diallyl Sulfide Against Ethanol-Induced Injury in Rat Adipose Tissue and Primary Human Adipocytes.

Alcohol Clin Exp Res 2017 Jun 16;41(6):1078-1092. Epub 2017 May 16.

Department of Biological Sciences , BITS Pilani, Hyderabad, India.

Background: Alcohol consumption is the fourth leading cause of death and disability worldwide. Several cellular pathways contribute to alcohol-mediated tissue injury. Adipose tissue apart from functioning as an endocrine organ secretes several hormones and cytokines known as adipokines that are known to play a significant role in alcohol-induced tissue damage. This study was designed to test the efficacy of diallyl sulfide (DAS) in regulating the alcohol-induced outcomes on adipose tissue.

Methods: Male Wistar rats were fed with 36% Lieber-DeCarli liquid diet containing ethanol (EtOH) for 4 weeks. Control rats were pair-fed with isocaloric diet containing maltodextrin instead of EtOH. During the last week of feeding protocol, the EtOH-fed rat group was given 200 mg/kg body weight of DAS through diet. We also studied DAS effect on isolated human primary adipocytes. Viability of human primary adipocytes on DAS treatment was assessed by MTT assay. Malondialdehyde (MDA), a marker of oxidative stress, was measured by HPLC and the thiobarbituric acid method. Expression of inflammatory genes and lipogenic genes was studied by qRT-PCR and Western blotting. Serum inflammatory gene expression was studied by ELISA.

Results: Our study results showed that DAS could alleviate EtOH-induced expression levels of proinflammatory and endoplasmic reticulum (ER) stress genes and improve adipose tissue mass and adipocyte morphology in male Wistar rats fed Lieber-DeCarli diet containing 6% EtOH. Further, we showed that DAS reduced the expression of lipogenic genes and improved lipid accumulation and adipocyte mass in human primary adipocytes treated with EtOH. Subsequently, we also showed that oxidative stress, as measured by the changes in MDA levels, was reduced in both male Wistar rats and human primary adipocytes treated with EtOH plus DAS.

Conclusions: Our study results prove that DAS is effective in ameliorating EtOH-induced damage to adipose tissue as evidenced by the reduction brought about by DAS in oxidative stress, ER stress, and proinflammatory gene expression levels. DAS treatment also regulated lipogenic gene expression levels, thereby reducing free fatty acid release. In conclusion, this study has clinical implications with respect to alcohol-induced adipose tissue injury among alcohol users.
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http://dx.doi.org/10.1111/acer.13398DOI Listing
June 2017

Genetic Polymorphisms of X-ray Repair Cross-Complementing Group 1 and Apurinic/Apyrimidinic Endonuclease-1 in Chronic Obstructive Pulmonary Disease.

Inflammation 2016 Jun;39(3):1198-204

Central Laboratory for Stem Cell Research & Translational Medicine, Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Kanchanbagh, Hyderabad, 500 058, Andhra Pradesh, India.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous collection of conditions characterized by irreversible expiratory airflow limitation. The disease is interspersed with exacerbations; periods of acute symptomatic, physiological, and functional deterioration. The present study was designed to investigate the role of X-ray cross-complementing group 1 (XRCC1) and apurinic/apyrimidinic endonuclease 1 (APE1) polymorphisms and the risk of COPD. Blood samples from 354 unrelated subject (age range 18-60 years; 156 with COPD, 198 healthy controls) were collected. Genomic DNA was isolated and genotyped for XRCC1 Arg399Gln and APE1 Asp148Glu using a confronting two pair primers polymerase chain reaction. GA genotype of XRCC1 gene was found to be predominant in the COPD group compared to controls with 1.86-fold increased risk for COPD (OR 1.86, 95 % CI 1.20-2.88, p = 0.0013). TG genotype of APE1 was found to be predominant in COPD group compared to controls with the difference being statistically significant (OR 1.68, 95 % CI 1.08-2.61, p = 0.0043). The GA haplotype was found to be predominant in COPD than controls with a 2.19-fold significant increase (OR 2.19, 95 % CI 1.46-3.28, p = 0.003). Polymorphism in XRCC1 and APE1 gene is associated with an increased risk of COPD.
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http://dx.doi.org/10.1007/s10753-016-0355-xDOI Listing
June 2016

Influence of BCL2-938 C>A promoter polymorphism and BCL2 gene expression on the progression of breast cancer.

Tumour Biol 2016 May 11;37(5):6905-12. Epub 2015 Dec 11.

Department of Genetics, Osmania University, Hyderabad, 500007, India.

BCL2 (B-cell leukemia/lymphoma 2) gene functions as antiapoptotic regulatory element and known to be associated with tumorigenesis. The SNP-938 (C>A) (rs2279115), located in the inhibitory P2 promoter of the BCL2 gene, influences differential binding affinities of transcriptional factors thereby affecting BCL2 expression. The present study is an attempt to evaluate the association between BCL2(-938C>A) polymorphism and clinical characteristics of breast cancer patients as well as to analyze BCL2 expression and Ki67 proliferation index with respect to the genotypes. One hundred ten primary breast cancer tumor tissues were genotyped for -938 C>A polymorphism through PCR-RFLP method as well as evaluated for BCL2 expression and ki67 proliferation index by immunohistochemistry. Evaluation of apoptosis level was performed by flowcytometry. The results revealed that AA genotype was associated with an increased risk (AA Vs AC + CC) by 2.86-fold (p = 0.07) for breast cancer development which reflected in elevated A allele frequency also. AA genotype was found to be predominant among BCL2 positive tumors as compared to BCL2 negative tumors. Further, AA genotype was found to be associated with advanced stage tumors, node positive status, and high Ki67 proliferation index compared to CA and CC genotypes indicating that elevated expression of BCL2 gene in the presence of A allele might be associated with decreased apoptosis and enhanced proliferation rate. AA genotype of BCL2-938C>A polymorphism might influence BCL2 gene expression there by associated with elevated risk for breast cancer progression. Probably, failure of apoptosis due to enhanced expression and antiapoptotic protein BCL2 might promote malignant growth.
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http://dx.doi.org/10.1007/s13277-015-4554-0DOI Listing
May 2016

LCN2 Promoter Methylation Status as Novel Predictive Marker for Microvessel Density and Aggressive Tumor Phenotype in Breast Cancer Patients.

Asian Pac J Cancer Prev 2015 ;16(12):4965-9

Department of Genetics, Osmania University, Kanchanbagh, India E-mail :

LCN2 (Lipocalin 2) is a 25 KD secreted acute phase protein, reported to be a novel regulator of angiogenesis in breast cancer. Up regulation of LCN2 had been observed in multiple cancers including breast cancer, pancreatic cancer and ovarian cancer. However, the role of LCN2 promoter methylation in the formation of microvessels is poorly understood. The aim of this study was to analyze the association of LCN 2 promoter methylation with microvessel formation and tumor cell proliferation in breast cancer patients. The LCN2 promoter methylation status was studied in 64 breast cancer tumors by methylation specific PCR (MSP). Evaluation of microvessel density (MVD) and Ki67 cell proliferation index was achieved by immunohistochemical staining using CD34 and MIB-1 antibodies, respectively. LCN2 promoter unmethylation status was observed in 43 (67.2%) of breast cancer patients whereas LCN2 methylation status was seen in 21 (32.8%). Further, LCN2 promoter unmethylation status was associated with aggressive tumor phenotype and elevated mean MVD in breast cancer patients.
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http://dx.doi.org/10.7314/apjcp.2015.16.12.4965DOI Listing
April 2016

Hepatic stem cells: A viable approach for the treatment of liver cirrhosis.

World J Stem Cells 2015 Jun;7(5):859-65

Md Aejaz Habeeb, Sandeep Kumar Vishwakarma, Avinash Bardia, Aleem Ahmed Khan, Center for Liver Research and Diagnostics, Deccan College of Medical Sciences, Hyderabad 500058, Andhra Pradesh, India.

Liver cirrhosis is characterized by distortion of liver architecture, necrosis of hepatocytes and regenerative nodules formation leading to cirrhosis. Various types of cell sources have been used for the management and treatment of decompensated liver cirrhosis. Knowledge of stem cells has offered a new dimension for regenerative therapy and has been considered as one of the potential adjuvant treatment modality in patients with end stage liver diseases (ESLD). Human fetal hepatic progenitor cells are less immunogenic than adult ones. They are highly propagative and challenging to cryopreservation. In our earlier studies we have demonstrated that fetuses at 10-18 wk of gestation age contain a large number of actively dividing hepatic stem and progenitor cells which possess bi-potent nature having potential to differentiate into bile duct cells and mature hepatocytes. Hepatic stem cell therapy for the treatment of ESLD is in their early stage of the translation. The emerging technology of decellularization and recellularization might offer a significant platform for developing bioengineered personalized livers to come over the scarcity of desired number of donor organs for the treatment of ESLD. Despite these significant advancements long-term tracking of stem cells in human is the most important subject nowadays in order to answer several unsettles issues regarding the route of delivery, the choice of stem cell type(s), the cell number and the time-point of cell delivery for the treatment in a chronic setting. Answering to these questions will further contribute to the development of safer, noninvasive, and repeatable imaging modalities that could discover better cell therapeutic approaches from bench to bed-side. Combinatorial approach of decellularization and nanotechnology could pave a way towards the better understanding in determination of cell fate post-transplantation.
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http://dx.doi.org/10.4252/wjsc.v7.i5.859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478632PMC
June 2015

Magnetic nanoparticle tagged stem cell transplantation in spinal cord injury: A promising approach for targeted homing of cells at the lesion site.

Neurol India 2015 May-Jun;63(3):460-1

Centre for Liver Research and Diagnostics, Central Laboratory for Stem Cell Research and Translational Medicine, Deccan College of Medical Sciences, Kanchanbagh; Centre for Cellular and Molecular Medicine, Salar E Millat Sultan Salahuddin Owaisi Research Centre, PEH, Shahalibada, Hyderabad, Telangana, India.

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http://dx.doi.org/10.4103/0028-3886.158294DOI Listing
June 2015

In vitro quantitative and relative gene expression analysis of pancreatic transcription factors Pdx-1, Ngn-3, Isl-1, Pax-4, Pax-6 and Nkx-6.1 in trans-differentiated human hepatic progenitors.

J Diabetes Investig 2014 Sep 29;5(5):492-500. Epub 2014 Jan 29.

Department of Zoology The Adony Arts and Science College Kurnool India.

Aims/introduction: Diabetes is a major health concern throughout the world because of its increasing prevalence in epidemic proportions. β-Cell deterioration in the pancreas is a crucial factor for the progression of diabetes mellitus. Therefore, the restoration of β-cell mass and its function is of vital importance for the development of effective therapeutic strategies and most accessible cell sources for the treatment of diabetes mellitus.

Materials And Methods: Human fetuses (12-20 weeks gestation age) were used to isolate human hepatic progenitor cells (hHPCs) from fetal liver using a two-step collagenase digestion method. Epithelial cell adhesion molecule-positive (EpCAM+ve)-enriched hHPCs were cultured in vitro and induced with 5-30 mmol/L concentration of glucose for 0-32 h. Pdx-1 expression and insulin secretion was analyzed using immunophenotypic and chemifluorescence assays, respectively. Relative gene expression was quantified in induced hHPCs, and compared with uninduced and pancreatic cells to identify the activated transcription factors (Pdx-1, Ngn-3, Isl-1, Pax-4, Pax-6 and Nkx-6.1) involved in β-cell production.

Results: EpCAM+ve cells derived from human fetal liver showed high in vitro trans-differentiation potential towards the β-cell phenotype with 23 mmol/L glucose induction after 24 h. The transcription factors showed eminent expression in induced cells. The expression level of transcription factors was found significantly high in 23 mmol/L-induced hHPCs as compared with the uninduced cells.

Conclusions: The present study has shown an exciting new insight into β-cell development from hHPCs trans-differentiation. Relative quantification of gene expression in trans-differentiated cells offers vast possibility for the production of a maximum number of functionally active pancreatic β-cells for a future cure of diabetes.
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http://dx.doi.org/10.1111/jdi.12193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188105PMC
September 2014

Repopulation of decellularized whole organ scaffold using stem cells: an emerging technology for the development of neo-organ.

J Artif Organs 2014 Dec 17;17(4):291-300. Epub 2014 Jul 17.

Centre for Liver Research and Diagnostics, Deccan College of Medical Sciences, Kanchanbagh, Hyderabad, 500 058, Andhra Pradesh, India,

Demand of donor organs for transplantation in treatment of organ failure is increasing. Hence there is a need to develop new strategies for the alternative sources of organ development. Attempts are being made to use xenogenic organs by genetic manipulation but the organ rejection against human always has been a major challenge for the survival of the graft. Advancement in the genetic bioengineering and combination of different allied sciences for the development of humanized organ system, the therapeutic influence of stem cell fraction on the reconstitution of organ architecture and their regenerative abilities in different tissues and organs provides a better approach to solve the problem of organ shortage. However, the available strategies for generating the organ/tissue scaffolds limit its application due to the absence of complete three-dimensional (3D) organ architecture, mechanical strength, long-term cell survival, and vascularization. Repopulation of whole decellularized organ scaffolds using stem cells has added a new dimension for creating new bioengineered organs. In recent years, several studies have demonstrated the potential application of decellularization and recellularization approach for the development of functional bio-artificial organs. With the help of established procedures for conditioning, extensive stem cells and organ engineering experiments/transplants for the development of humanized organs will allow its preclinical evaluation for organ regeneration before translation to the clinic. This review focuses on the major aspects of organ scaffold generation and repopulation of different types of whole decellularized organ scaffolds using stem cells for the functional benefit and their confines.
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http://dx.doi.org/10.1007/s10047-014-0780-2DOI Listing
December 2014
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