Shashank Chetty

All Publications

• Evaluating the therapeutic potential of different sources of mesenchymal stem cells in acute respiratory distress syndrome. Stem cell research & therapy Regmi, S., Ganguly, A., Pathak, S., Primavera, R., Chetty, S., Wang, J., Patel, S., Thakor, A. S. 2024; 15 (1): 385

  Abstract

  Mesenchymal stem/stromal cells (MSCs) have attracted interest as a potential therapy given their anti-inflammatory and immunomodulatory properties. However, clinical trials using MSCs for acute respiratory distress syndrome (ARDS) have produced mixed and inconclusive data. In previous work, we performed a "head-to-head" comparison between different sources of MSCs and showed that each source had a unique genomic and proteomic "signature".This study investigated which sources of MSC: bone marrow derived-MSCs (BM-MSCs), adipose tissue derived-MSCs (AD-MSCs) and umbilical cord derived-MSCs (UC-MSCs)  would be the optimal candidate to be used as a therapy in an LPS-induced mouse model of ARDS. Immune cells assessment, tissue transcriptomics, animal survival, and endothelial-epithelial barrier assessment were used to evaluate their effects.When comparing the three most commonly used MSC sources, we found that UC-MSCs exhibited greater efficacy compared to other MSCs in improving animal survival, mitigating epithelial/endothelial damage, decreasing lung inflammation via reducing neutrophil infiltration, T cell proliferation, and M1 polarization. Bulk RNA sequencing of lung tissue also showed that UC-MSCs have the capability to downregulate extracellular trap formation, by the downregulation of key genes like Elane and Padi4. Notably, treatment with UC-MSCs demonstrated a significant reduction in Fc-γ R mediated phagocytosis, which has been associated with monocyte pyroptosis and intense inflammation in the context of COVID-19.Our findings suggest that UC-MSCs are an optimal source of MSC to treat acute inflammatory conditions in the lungs, such as ARDS.

  View details for DOI 10.1186/s13287-024-03977-w

  View details for PubMedID 39468662

  View details for PubMedCentralID PMC11520775

• Time-course analysis of cisplatin induced AKI in preclinical models: implications for testing different sources of MSCs. Journal of translational medicine Ganguly, A., Chetty, S., Primavera, R., Levitte, S., Regmi, S., Dulken, B. W., Sutherland, S. M., Angeles, W., Wang, J., Thakor, A. S. 2024; 22 (1): 789

  Abstract

  Kidneys are at risk from drug-induced toxicity, with a significant proportion of acute kidney injury (AKI) linked to medications, particularly cisplatin. Existing cytoprotective drugs for cisplatin-AKI carry side effects, prompting a search for better biological therapies. Mesenchymal Stem Cells (MSCs) are under consideration given their regenerative properties, yet their clinical application has not achieved their full potential, mainly due to variability in the source of MSC tested. In addition, translating treatments from rodent models to humans remains challenging due to a lack of standardized dosing and understanding potential differential responses to cisplatin between animal strains.In the current study, we performed a time-course analysis of the effect of cisplatin across different mouse strains and evaluated gender related differences to create a robust preclinical model that could then be used to explore the therapeutic efficacy of different sources of MSCs for their ability to reverse AKI.Our data indicated that different mouse strains produce differential responses to the same cisplatin dosing regimen. Despite this, we did not observe any gender-related bias towards cisplatin nephrotoxicity. Furthermore, our time-course analysis identified that cisplatin-induced inflammation was driven by a strong CXCL1 response, which was used as a putative biomarker to evaluate the comparative therapeutic efficacy of different MSC sources in reversing AKI. Our data indicates that UC-MSCs have a stronger anti-inflammatory effect compared to BM-MSCs and AD-MSCs, which helped to ameliorate cisplatin-AKI.Overall, our data underscores the importance of using an optimized preclinical model of cisplatin-AKI to test different therapies. We identified CXCL1 as a potential biomarker of cisplatin-AKI and identified the superior efficacy of UC-MSCs in mitigating cisplatin-AKI.

  View details for DOI 10.1186/s12967-024-05439-6

  View details for PubMedID 39192240

  View details for PubMedCentralID 4146684

• Therapeutic potential of exosomes derived from mesenchymal stem cells for treatment of systemic lupus erythematosus. Journal of inflammation (London, England) Samavati, S. F., Yarani, R., Kiani, S., HoseinKhani, Z., Mehrabi, M., Levitte, S., Primavera, R., Chetty, S., Thakor, A. S., Mansouri, K. 2024; 21 (1): 20

  Abstract

  Autoimmune diseases are caused by an imbalance in the immune system, producing autoantibodies that cause inflammation leading to tissue damage and organ dysfunction. Systemic Lupus Erythematosus (SLE) is one of the most common autoimmune diseases and a major contributor to patient morbidity and mortality. Although many drugs manage the disease, curative therapy remains elusive, and current treatment regimens have substantial side effects. Recently, the therapeutic potential of exosomes has been extensively studied, and novel evidence has been demonstrated. A direct relationship between exosome contents and their ability to regulate the immune system, inflammation, and angiogenesis. The unique properties of extracellular vesicles, such as biomolecule transportation, biodegradability, and stability, make exosomes a promising treatment candidate for autoimmune diseases, particularly SLE. This review summarizes the structural features of exosomes, the isolation/purification/quantification method, their origin, effect, immune regulation, a critical consideration for selecting an appropriate source, and their therapeutic mechanisms in SLE.

  View details for DOI 10.1186/s12950-024-00381-2

  View details for PubMedID 38867277

  View details for PubMedCentralID 1447637

• Precision Delivery of Human Bone Marrow-Derived Mesenchymal Stem Cells Into the Pancreas Via Intra-arterial Injection Prevents the Onset of Diabetes. Stem cells translational medicine Primavera, R., Regmi, S., Yarani, R., Levitte, S., Wang, J., Ganguly, A., Chetty, S., Guindani, M., Ricordi, C., Meyer, E., Thakor, A. S. 2024

  Abstract

  Mesenchymal stem cells (MSCs) are a promising therapy to potentially treat diabetes given their potent anti-inflammatory and immune-modulatory properties. While these regenerative cells have shown considerable promise in cell culture, their clinical translation has been challenging. In part, this can be attributed to these cells not reaching the pancreas to exert their regenerative effects following conventional intravenous (IV) injection, with the majority of cells being trapped in the lungs in the pulmonary first-pass effect. In the present study, we will therefore examine whether direct delivery of MSCs to the pancreas via an intra-arterial (IA) injection can improve their therapeutic efficacy. Using a mouse model, in which repetitive low doses of STZ induced a gentle, but progressive, hyperglycemia, we tested bone marrow-derived MSCs (BM-MSCs) which we have shown are enriched with pro-angiogenic and immunomodulatory factors. In cell culture studies, BM-MSCs were shown to preserve islet viability and function following exposure to proinflammatory cytokines (IFN-gamma, IL-1beta, and TNF-alpha) through an increase in pAkt. When tested in our animal model, mice receiving IV BM-MSCs were not able to mitigate the effects of STZ, however those which received the same dose and batch of cells via IA injection were able to maintain basal and dynamic glycemic control, to similar levels as seen in healthy control animals, over 10 days. This study shows the importance of considering precision delivery approaches to ensure cell-based therapies reach their intended targets to enable them to exert their therapeutic effects.

  View details for DOI 10.1093/stcltm/szae020

  View details for PubMedID 38530131

• β Cell and Autophagy: What Do We Know? Biomolecules Mohammadi-Motlagh, H. R., Sadeghalvad, M., Yavari, N., Primavera, R., Soltani, S., Chetty, S., Ganguly, A., Regmi, S., Fløyel, T., Kaur, S., Mirza, A. H., Thakor, A. S., Pociot, F., Yarani, R. 2023; 13 (4)

  Abstract

  Pancreatic β cells are central to glycemic regulation through insulin production. Studies show autophagy as an essential process in β cell function and fate. Autophagy is a catabolic cellular process that regulates cell homeostasis by recycling surplus or damaged cell components. Impaired autophagy results in β cell loss of function and apoptosis and, as a result, diabetes initiation and progress. It has been shown that in response to endoplasmic reticulum stress, inflammation, and high metabolic demands, autophagy affects β cell function, insulin synthesis, and secretion. This review highlights recent evidence regarding how autophagy can affect β cells' fate in the pathogenesis of diabetes. Furthermore, we discuss the role of important intrinsic and extrinsic autophagy modulators, which can lead to β cell failure.

  View details for DOI 10.3390/biom13040649

  View details for PubMedID 37189396

  View details for PubMedCentralID PMC10136307

• Integrated transcriptome-proteome analyses of human stem cells reveal source-dependent differences in their regenerative signature. Stem cell reports Ganguly, A., Swaminathan, G., Garcia-Marques, F., Regmi, S., Yarani, R., Primavera, R., Chetty, S., Bermudez, A., Pitteri, S. J., Thakor, A. S. 2022

  Abstract

  Mesenchymal stem cells (MSCs) are gaining increasing prominence as an effective regenerative cellular therapy. However, ensuring consistent and reliable effects across clinical populations has proved to be challenging. In part, this can be attributed to heterogeneity in the intrinsic molecular and regenerative signature of MSCs, which is dependent on their source of origin. The present work uses integrated omics-based profiling, at different functional levels, to compare the anti-inflammatory, immunomodulatory, and angiogenic properties between MSCs from neonatal (umbilical cord MSC [UC-MSC]) and adult (adipose tissue MSC [AD-MSC], and bone marrow MSC [BM-MSC]) sources. Using multi-parametric analyses, we identified that UC-MSCs promote a more robust host innate immune response; in contrast, adult-MSCs appear to facilitate remodeling of the extracellular matrix (ECM) with stronger activation of angiogenic cascades. These data should help facilitate the standardization of source-specific MSCs, such that their regenerative signatures can be confidently used to target specific disease processes.

  View details for DOI 10.1016/j.stemcr.2022.11.006

  View details for PubMedID 36493779

• Umbilical cord mesenchymal stromal cells-from bench to bedside. Frontiers in cell and developmental biology Chetty, S., Yarani, R., Swaminathan, G., Primavera, R., Regmi, S., Rai, S., Zhong, J., Ganguly, A., Thakor, A. S. 2022; 10: 1006295

  Abstract

  In recent years, mesenchymal stromal cells (MSCs) have generated a lot of attention due to their paracrine and immuno-modulatory properties. mesenchymal stromal cells derived from the umbilical cord (UC) are becoming increasingly recognized as having increased therapeutic potential when compared to mesenchymal stromal cells from other sources. The purpose of this review is to provide an overview of the various compartments of umbilical cord tissue from which mesenchymal stromal cells can be isolated, the differences and similarities with respect to their regenerative and immuno-modulatory properties, as well as the single cell transcriptomic profiles of in vitro expanded and freshly isolated umbilical cord-mesenchymal stromal cells. In addition, we discuss the therapeutic potential and biodistribution of umbilical cord-mesenchymal stromal cells following systemic administration while providing an overview of pre-clinical and clinical trials involving umbilical cord-mesenchymal stromal cells and their associated secretome and extracellular vesicles (EVs). The clinical applications of umbilical cord-mesenchymal stromal cells are also discussed, especially in relation to obstacles and potential solutions for their effective translation from bench to bedside.

  View details for DOI 10.3389/fcell.2022.1006295

  View details for PubMedID 36313578

  View details for PubMedCentralID PMC9597686

• Mesenchymal stromal cells for the treatment of Alzheimer's disease: Strategies and limitations. Frontiers in molecular neuroscience Regmi, S., Liu, D. D., Shen, M., Kevadiya, B. D., Ganguly, A., Primavera, R., Chetty, S., Yarani, R., Thakor, A. S. 2022; 15: 1011225

  Abstract

  Alzheimer's disease (AD) is a major cause of age-related dementia and is characterized by progressive brain damage that gradually destroys memory and the ability to learn, which ultimately leads to the decline of a patient's ability to perform daily activities. Although some of the pharmacological treatments of AD are available for symptomatic relief, they are not able to limit the progression of AD and have several side effects. Mesenchymal stem/stromal cells (MSCs) could be a potential therapeutic option for treating AD due to their immunomodulatory, anti-inflammatory, regenerative, antioxidant, anti-apoptotic, and neuroprotective effects. MSCs not only secret neuroprotective and anti-inflammatory factors to promote the survival of neurons, but they also transfer functional mitochondria and miRNAs to boost their bioenergetic profile as well as improve microglial clearance of accumulated protein aggregates. This review focuses on different clinical and preclinical studies using MSC as a therapy for treating AD, their outcomes, limitations and the strategies to potentiate their clinical translation.

  View details for DOI 10.3389/fnmol.2022.1011225

  View details for PubMedID 36277497

• Human Umbilical Cord Wharton's Jelly-Derived Mesenchymal Stem Cells Labeled with Mn2+ and Gd3+ Co-Doped CuInS2-ZnS Nanocrystals for Multimodality Imaging in a Tumor Mice Model ACS APPLIED MATERIALS & INTERFACES Chetty, S., Praneetha, S., Murugan, A., Govarthanan, K., Verma, R. 2020; 12 (3): 3415–29

  Abstract

  Mesenchymal stem cell (MSCs) therapy has recently received profound interest as a targeting platform in cancer theranostics because of inherent tumor-homing abilities. However, the terminal tracking of MSCs engraftment by fluorescent in situ hybridization, immuno-histochemistry, and flow-cytometry techniques to translate into clinics is still challenging because of a dearth of inherent MSCs-specific markers and FDA approval for genetic modifications of MSCs. To address this challenge, a cost-effective noninvasive imaging technology based on multifunctional nanocrystals (NCs) with enhanced detection sensitivity, spatial-temporal resolution, and deep-tissue diagnosis is needed to be developed to track the transplanted stem cells. A hassle-free labeling of human umbilical cord Wharton's Jelly (WJ)-derived MSCs with Mn2+ and Gd3+ co-doped CuInS2-ZnS (CIS-ZMGS) NCs has been demonstrated in 2 h without requiring an electroporation process or transfection agents. It has been found that WJ-MSCs labeling did not affect their multilineage differentiation (adipocyte, osteocyte, chondrocyte), immuno-phenotypes (CD44+, CD105+, CD90+), protein (β-actin, vimentin, CD73, α-SMCA), and gene expressions. Interestingly, CIS-ZMGS-NCs-labeled WJ-MSCs exhibit near-infrared (NIR) fluorescence with a quantum yield of 84%, radiant intensity of ∼3.999 × 1011 (p/s/cm2/sr)/(μW/cm2), magnetic relaxivity (longitudinal r1 = 2.26 mM-1 s-1, transverse r2 = 16.47 mM-1 s-1), and X-ray attenuation (78 HU) potential for early noninvasive multimodality imaging of a subcutaneous melanoma in B16F10-tumor-bearing C57BL/6 mice in 6 h. The ex vivo imaging and inductively coupled plasma mass-spectroscopy analyses of excised organs along with confocal microscopy and immunofluorescence of tumor results also significantly confirmed the positive tropism of CIS-ZMGS-NCs-labeled WJ-MSCs in the tumor environment. Hence, we propose the magnetofluorescent CIS-ZMGS-NCs-labeled WJ-MSCs as a next-generation nanobioprobe of three commonly used imaging modalities for stem cell-assisted anticancer therapy and tracking tissue/organ regenerations.

  View details for DOI 10.1021/acsami.9b19054

  View details for Web of Science ID 000509428300011

  View details for PubMedID 31875453

• Noninvasive Tracking and Regenerative Capabilities of Transplanted Human Umbilical Cord-Derived Mesenchymal Stem Cells Labeled with I-III-IV Semiconducting Nanocrystals in Liver-Injured Living Mice ACS APPLIED MATERIALS & INTERFACES Chetty, S., Praneetha, S., Govarthanan, K., Verma, R., Murugan, A. 2019; 11 (9): 8763–78

  Abstract

  Acute liver injury is a critical syndrome ascribed to prevalent death of hepatocytes and imperatively requires liver transplantation. Such a methodology is certainly hampered due to the deficit of healthy donors. In this regard, stem cell-based regenerative therapies are attractive in repairing injured tissues and organs for medical applications. However, it is crucial to understand the migration, engraftment, and regeneration capabilities of transplanted stem cells in the living animal models. For the first time, we demonstrate rapid labeling of umbilical cord-derived mesenchymal stem cells (MSCs) with near-infrared (NIR)-fluorescent CuInS2-ZnS nanocrystals (CIZS-NCs) to develop innovative nanobioconjugates (MSCs-CIZS-NBCs) that exhibit 98% labeling efficiency. Before nanobioconjugate synthesis, the pristine CIZS-NCs were prepared via a two-step, hot-injection, rapid and low-cost domestic-microwave-refluxing (MW-R) method within 6 min. The as-synthesized CIZS-NCs display high photoluminescence quantum yield (∼88%) and long-lived lifetime (23.4 μs). In contrast to unlabeled MSCs, the MSCs-CIZS nanobioconjugates show excellent biocompatibility without affecting the stemness, as confirmed by cell viability, immunophenotyping (CD44+, CD105+, CD90+), multi-lineage-specific gene expressions, and differentiation into adipocytes, osteocytes, and chondrocytes. The in vivo fluorescence tracking analyses revealed that the MSCs-CIZS-NBCs after tail-vein injection were initially trapped in the lungs and gradually engrafted in the injured liver within 2 h. The regeneration potential of MSCs-CIZS-NBCs was confirmed via renewal of the portal tract composed of portal veins, bile ducts, and hepatic arteries around the hepatocytes. Consequently, no apparent inflammations, necrosis, or apoptosis was observed in the acetaminophen (APAP)-induced liver-injured BALB/c mice model over 3 days after transplantation, as corroborated using laser-scanning confocal microscopy and histopathological and hematological analyses. Hence, our innovative NIR-fluorescent MSCs-CIZS-NBCs offer an off-the-self technology for noninvasive tracking of transplanted MSCs in an acute-liver-injured animal model for future image-guided cell-therapies.

  View details for DOI 10.1021/acsami.8b19953

  View details for Web of Science ID 000460996900010

  View details for PubMedID 30741534

• Microwave-Assisted Synthesis of Quasi-Pyramidal CuInS2-ZnS Nanocrystals for Enhanced Near-Infrared Targeted Fluorescent Imaging of Subcutaneous Melanoma ADVANCED BIOSYSTEMS Chetty, S., Praneetha, S., Murugan, A., Govarthanan, K., Verma, R. S. 2019; 3 (1): e1800127

  Abstract

  Near-infrared (NIR) fluorescent CuInS2 -ZnS nanocrystals (CIZS NCs) are synthesized via an ultra-fast, non-injection microwave (MW)-assisted nanoalloying process at 230 ºC within 5 min using 1-dodecanethiol (DDT) as both the sulfur source and solvent under solvothermal (ST) condition. The structural and surface analyses reveal that DDT-functionalized CIZS NCs exhibit quasi-pyramids of tetragonal-phase with well-defined facets. The DDT-functionalized CIZS NCs present a photoluminescence quantum yield (PLQY) of 76% and a long-lived fluorescence lifetime of ≈0.6 µs in organic-phase. Subsequently, DDT-functionalized CIZS NCs are phase-transferred via ligand-exchange using 11-mercaptoundecanoic acid (MUA) into water-soluble MUA-CIZS NCs that exhibit a substantial PLQY of 55%. In addition, the NIR-fluorescent MUA-functionalized CIZS NCs in conjugation with folic acid (FA), as a tumor-targeting ligand, demonstrates enhanced tumor-targeted imaging ability. The FA-MUA-CIZS NC conjugates exhibit a cell viability of ≈75% even at the highest concentration of 1 mg mL-1 and a labeling efficiency of 95.4%. The in vivo imaging results corroborate that FA-MUA-CIZS NCs conjugates are actively targeted to folate receptor-positive B16F10 tumor-bearing C57BL/6 mice in 2 h. The histopathological and hematological studies confirm no significant changes in tissue architecture and blood biochemical parameters. The confocal microscopy studies reveal deep penetration and uniform distribution of FA-MUA-CIZS NCs conjugates in subcutaneous melanoma.

  View details for DOI 10.1002/adbi.201800127

  View details for Web of Science ID 000455812800008

  View details for PubMedID 32627345

• Transition Metal Ion (Mn2+, Fe2+, Co2+, and Ni2+)-Doped Carbon Dots Synthesized via Microwave-Assisted Pyrolysis: A Potential Nanoprobe for Magneto-fluorescent Dual-Modality Bioimaging ACS BIOMATERIALS SCIENCE & ENGINEERING Pakkath, S., Chetty, S., Selvarasu, P., Murugan, A., Kumar, Y., Periyasamy, L., Santhakumar, M., Sadras, S., Santhakumar, K. 2018; 4 (7): 2582–96

  View details for DOI 10.1021/acsbiomaterials.7b00943

  View details for Web of Science ID 000438475500032

• Sustainable, Rapid Synthesis of Bright-Luminescent CuInS2-ZnS Alloyed Nanocrystals: Multistage Nano-xenotoxicity Assessment and Intravital Fluorescence Bioimaging in Zebrafish-Embryos (vol 6, 26078, 2016) SCIENTIFIC REPORTS Chetty, S., Praneetha, S., Basu, S., Sachidanandan, C., Murugan, A. 2016; 6: 28607

  View details for DOI 10.1038/srep28607

  View details for Web of Science ID 000378492100001

  View details for PubMedID 27345563

  View details for PubMedCentralID PMC4921864

• One-pot microwave-assisted in situ reduction of Ag+ and Au3+ ions by Citrus limon extract and their carbon-dots based nanohybrids: a potential nano-bioprobe for cancer cellular imaging RSC ADVANCES Sajid, P. A., Chetty, S., Praneetha, S., Murugan, A., Kumar, Y., Periyasamy, L. 2016; 6 (105): 103482–90

  View details for DOI 10.1039/c6ra24033j

  View details for Web of Science ID 000387726500080