Regenerative – ASSET

Development of Three-dimensional Brown Adipose Tissue Organoids From Human Pluripotent Stem Cells

admin — Thu, 05 Dec 2024 02:06:59 +0000

Brown adipose tissue (BAT) plays a crucial role in energy regulation and adaptive thermogenesis generating heat through UCP1 activation. This unique capability makes BAT a promising therapeutic target for metabolic diseases such as type 2 diabetes, obesity, and other related metabolic disorders. Understanding the developmental pathways of BAT is critical for designing novel therapeutic strategies aimed at enhancing its regenerative potential or functional activity. Recent advances in in vitro differentiation protocols, such as the approach developed by Jyoti Rao, have enabled the generation of brown adipocytes from induced pluripotent stem cells (iPSCs) by imitating key steps of BAT developmental pathways. However, significant limitations remain. These include the prolonged duration required for differentiation and the challenges of engrafting these adipocytes due to their fragile structure as single cells. Consequently, traditional cell therapy approaches, which rely on dissociating cells into single-cell suspensions for injection, are not feasible for effective BAT transplantation. To address these limitations, we propose using the “somitoids” model developed by Yuchuan Miao. Somitoids are three-dimensional structures that recapitulate early embryonic somite formation, a critical stage in the derivation of BAT precursors. By using somitoids as a starting point, we aim to reconstruct the full developmental pathway leading to the formation of BAT organoids. This novel approach has the potential to produce more physiologically relevant BAT tissue, both structurally and functionally, compared to current methods.

Authors List :

Amine Bouchekioua

Presenting Author :

Amine Bouchekioua

Affiliations :

Harvard Medical School, Brigham and Women's Hospital, University of Lille

Email :

abouchekioua@bwh.harvard.edu

Key Words (5 Words Maximum) :

Cell therapy; iPSCs; Developmental Biology; Brown Adipose Tissue; Diabetes

Cryptolepine: A Promising Naturally-derived Alkaloid Inhibits Breast Cancer Progression by blocking cell cycle progression and inducing apoptosis

admin — Wed, 13 Dec 2023 14:55:53 +0000

Breast cancer (BC), the second most common cause of cancer-related deaths, remains a significant threat to the health and wellness of women worldwide. Even with new treatment options like chemotherapy and surgery, breast cancer’s lethality is still concerning. Natural compounds are considered to be a better therapeutic option for breast carcinoma because they are anticipated to have less side effects and to be more selective in targeting important proteins linked to the aberrant activation of pathways in breast cancer. A new indoloquinoline alkaloid found in the roots of the Periplocaceae family plant Cryptolepis sanguinolenta (Lindl.) Schltr known as cryptolepine has been shown to have the anticancer activity but this compound is poorly explored in breast cancer. However, little is known about the molecular processes via which this material functions in breast cancer. Earlier we have shown that Cryptolepine targets TOP2A which is highly overexpressed in breast cancer tissues and its overexpression correlates with worse overall survival and relapse-free survival in breast cancer patients. Consequently, our objective in this study was to investigate the molecular mechanism that Cryptolepine’s employs to inhibit breast carcinoma. We used the in-vitro and computational studies to look at the mechanism of action of cryptolepine in breast cancer. The results showed that the drug activated the P53 signalling pathway, which led to apoptosis and cell cycle arrest in breast cancer cells. Therefore, targeting P53, TOP2A in combination with other therapeutic agents will significantly enhance the response of BC patients to therapy and reduce the development of chemoresistance. This will help to reduce the burden on existing therapies, which are also currently ineffective due to a number of side effects and the emergence of drug resistance.

Authors List :

Manzoor A Mir and Hina Qayoom

Presenting Author :

Manzoor A Mir

Affiliations :

Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar J&K India

Email :

drmanzoor@kashmiruniversity.ac.in

Key Words (5 Words Maximum) :

Breast cancer, Cryptolepine, P53 pathway, Cell cycle arrest, TOP2A, Apoptosis

Role of Immune Cells in Obesity and Type 2 Diabetes

admin — Mon, 11 Dec 2023 01:14:06 +0000

The global prevalence of obesity and type 2 diabetes has reached alarming levels, posing a substantial public health burden. Recent research has exclusively explored a previously underappreciated aspect of these metabolic disorders-the pivotal role played by immune cells, particularly macrophages, in the pathogenesis of insulin resistance. Insulin resistance precede and predict risk of type 2 diabetes. Adipose tissue, previously considered a mere energy storage organ, has emerged as an active immune organ contributing to metabolic dysregulation. Phenotype-switching of macrophages within adipose tissue, shifting from an anti-inflammatory M2 phenotype to a pro-inflammatory M1 phenotype contribute to the development of obesity-induced insulin resistance. It is important to explore the role of adipose tissue macrophages in initiating and sustaining low-grade inflammation, which contributes to insulin resistance. Our team is actively engaged in aiming to understand cell-cell communications among adipocytes, immune cells, and resident stromal cells within adipose tissue and in skeletal muscle. In addition to the adipose tissue milieu, I will discuss the systemic effects of immune cell dysregulation in obesity and skeletal muscle injury, including the role of macrophage-derived regulatory factors in promoting insulin resistance. In conclusion, understanding the integral role of immune cells, particularly macrophages, in obesity and type 2 diabetes pathophysiology offers a promising avenue for novel therapeutic strategies. In this presentation, my aims to provide a comprehensive overview of current research in this field, fostering a deeper appreciation for the crosstalk between immunology and metabolism in these prevalent metabolic disorders.

Authors List :

Allah Nawaz, Muhammad Bilal, Muhammad Rahil Aslam, Kazuyuki Tobe

Presenting Author :

Allah Nawaz

Affiliations :

Section on Integrative Physiology and Metabolism Joslin Diabetes Center, Harvard Medical School, Harvard University, Boston, MA 02215, USA.

Email :

allah.nawaz@joslin.harvard.edu

Key Words (5 Words Maximum) :

Obesity, Type 2 Diabetes, Macrophages, Stem cells

Reconstructing human brown fat developmental trajectory in vitro

admin — Wed, 15 Nov 2023 06:14:35 +0000

Brown adipocytes (BAs) represent a specialized cell type that is able to uncouple nutrient catabolism from ATP generation to dissipate energy as heat. In humans, the brown fat tissue is composed of discrete depots found throughout the neck and trunk region. BAs originate from a precursor common to skeletal muscle, but their developmental trajectory remains poorly understood. Here, we used single-cell RNA sequencing to charac- terize the development of interscapular brown fat in mice. Our analysis identified a transient stage of BA dif- ferentiation characterized by the expression of the transcription factor GATA6. We show that recapitulating the sequence of signaling cues identified in mice can lead to efficient differentiation of BAs in vitro from human pluripotent stem cells. These precursors can in turn be efficiently converted into functional BAs that can respond to signals mimicking adrenergic stimuli by increasing their metabolism, resulting in heat production.

Authors List :

Jyoti Rao1, Yannis Djeffal, Jerome Chal, Fabio Marchianò, Chih-Hao Wang, Ziad Al Tanoury, Svetlana Gapon, Alicia Mayeuf-Louchart, Ian Glass, Elizabeth M. Sefton, Bianca Habermann, Gabrielle Kardon, Fiona M. Watt, Yu-Hua Tseng, Olivier Pourquié

Presenting Author :

Amine Bouchekioua (not author of this paper, but new PhD student in charge of this project)

Affiliations :

Brigham and Women's Hospital; Harvard Medical School

Email :

abouchekioua@bwh.harvard.edu

Key Words (5 Words Maximum) :

iPSCs ; Brown Adipose Tissue ; Cell therapy

Cell based therapies for cancer: From Innovation to Translation

admin — Sun, 04 Dec 2022 07:21:14 +0000

Cell based therapies are emerging as a promising strategy for cancer. We have developed cell surface receptor targeted adult stem cells, cancer cells and T cells expressing novel bi-functional immunomodulatory proteins and releasing oncolytic viruses. Using our recently established tumor models that mimic clinical settings, we have explored the fate and efficacy of different engineered cell based therapies. Our findings demonstrate the strength of using innovative approaches and clinically relevant preclinical models that pave a path for clinical translation. This presentation provides data and rationale for assessing combined cell based studies in preclinical studies and translating the most promising studies into the clinic.

Authors List :

Khalid Shah

Presenting Author :

Khalid Shah

Affiliations :

Department of Neurosurgery, Harvard Medical School, Center for Stem Cell & Translational Immunotherapy Brigham and Women's Hospital, Harvard Medical School, Harvard Stem Cell Institute

Email :

KSHAH@bwh.harvard.edu

Key Words (5 Words Maximum) :

Stem cells, immunotherapy, engineered cells, translation, cell receptors