Fabrication of a three-dimensional bone marrow niche-like acute myeloid Leukemia disease model by an automated and controlled process using a robotic multicellular bioprinting system.

3D bone marrow (niche-like) Disease model 3D multicellular bioprinting Acute Myeloid Leukemia Ultrashort self-assembling peptide scaffolds Whole transcriptome analysis

Journal

Biomaterials research
ISSN: 1226-4601
Titre abrégé: Biomater Res
Pays: England
ID NLM: 101650636

Informations de publication

Date de publication:
06 Nov 2023
Historique:
received: 28 08 2023
accepted: 29 10 2023
medline: 7 11 2023
pubmed: 7 11 2023
entrez: 7 11 2023
Statut: epublish

Résumé

Acute myeloid leukemia (AML) is a hematological malignancy that remains a therapeutic challenge due to the high incidence of disease relapse. To better understand resistance mechanisms and identify novel therapies, robust preclinical models mimicking the bone marrow (BM) microenvironment are needed. This study aimed to achieve an automated fabrication process of a three-dimensional (3D) AML disease model that recapitulates the 3D spatial structure of the BM microenvironment and applies to drug screening and investigational studies. To build this model, we investigated a unique class of tetramer peptides with an innate ability to self-assemble into stable hydrogel. An automated robotic bioprinting process was established to fabricate a 3D BM (niche-like) multicellular AML disease model comprised of leukemia cells and the BM's stromal and endothelial cellular fractions. In addition, monoculture and dual-culture models were also fabricated. Leukemia cell compatibility, functionalities (in vitro and in vivo), and drug assessment studies using our model were performed. In addition, RNAseq and gene expression analysis using TaqMan arrays were also performed on 3D cultured stromal cells and primary leukemia cells. The selected peptide hydrogel formed a highly porous network of nanofibers with mechanical properties similar to the BM extracellular matrix. The robotic bioprinter and the novel quadruple coaxial nozzle enabled the automated fabrication of a 3D BM niche-like AML disease model with controlled deposition of multiple cell types into the model. This model supported the viability and growth of primary leukemic, endothelial, and stromal cells and recapitulated cell-cell and cell-ECM interactions. In addition, AML cells in our model possessed quiescent characteristics with improved chemoresistance attributes, resembling more the native conditions as indicated by our in vivo results. Moreover, the whole transcriptome data demonstrated the effect of 3D culture on enhancing BM niche cell characteristics. We identified molecular pathways upregulated in AML cells in our 3D model that might contribute to AML drug resistance and disease relapse. Our results demonstrate the importance of developing 3D biomimicry models that closely recapitulate the in vivo conditions to gain deeper insights into drug resistance mechanisms and novel therapy development. These models can also improve personalized medicine by testing patient-specific treatments.

Sections du résumé

BACKGROUND BACKGROUND
Acute myeloid leukemia (AML) is a hematological malignancy that remains a therapeutic challenge due to the high incidence of disease relapse. To better understand resistance mechanisms and identify novel therapies, robust preclinical models mimicking the bone marrow (BM) microenvironment are needed. This study aimed to achieve an automated fabrication process of a three-dimensional (3D) AML disease model that recapitulates the 3D spatial structure of the BM microenvironment and applies to drug screening and investigational studies.
METHODS METHODS
To build this model, we investigated a unique class of tetramer peptides with an innate ability to self-assemble into stable hydrogel. An automated robotic bioprinting process was established to fabricate a 3D BM (niche-like) multicellular AML disease model comprised of leukemia cells and the BM's stromal and endothelial cellular fractions. In addition, monoculture and dual-culture models were also fabricated. Leukemia cell compatibility, functionalities (in vitro and in vivo), and drug assessment studies using our model were performed. In addition, RNAseq and gene expression analysis using TaqMan arrays were also performed on 3D cultured stromal cells and primary leukemia cells.
RESULTS RESULTS
The selected peptide hydrogel formed a highly porous network of nanofibers with mechanical properties similar to the BM extracellular matrix. The robotic bioprinter and the novel quadruple coaxial nozzle enabled the automated fabrication of a 3D BM niche-like AML disease model with controlled deposition of multiple cell types into the model. This model supported the viability and growth of primary leukemic, endothelial, and stromal cells and recapitulated cell-cell and cell-ECM interactions. In addition, AML cells in our model possessed quiescent characteristics with improved chemoresistance attributes, resembling more the native conditions as indicated by our in vivo results. Moreover, the whole transcriptome data demonstrated the effect of 3D culture on enhancing BM niche cell characteristics. We identified molecular pathways upregulated in AML cells in our 3D model that might contribute to AML drug resistance and disease relapse.
CONCLUSIONS CONCLUSIONS
Our results demonstrate the importance of developing 3D biomimicry models that closely recapitulate the in vivo conditions to gain deeper insights into drug resistance mechanisms and novel therapy development. These models can also improve personalized medicine by testing patient-specific treatments.

Identifiants

DOI: 10.1186/s40824-023-00457-9 PMID: 37932837 PMC: PMC10626721
pubmed: 37932837
doi: 10.1186/s40824-023-00457-9
pii: 10.1186/s40824-023-00457-9
pmc: PMC10626721
doi:

Types de publication

Journal Article

Langues

eng

Pagination

111

Subventions

Organisme : KAUST-smart health initiative
ID : REI/1/4938
Organisme : KAUST-KAU initiative, King Abdulaziz University
ID : joint project number: JP-19-003

Informations de copyright

© 2023. The Author(s).

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Auteurs

Dana M Alhattab (DM)

Laboratory for Nanomedicine, Bioengineering Program, Division of Biological & Environmental Science & Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia.
Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia.
KAUST Smart Health Initiative (KSHI), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia.

Ioannis Isaioglou (I)

Cell Migration and Signaling Laboratory, Bioscience Program, Division of Biological & Environmental Science & Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.

Salwa Alshehri (S)

Laboratory for Nanomedicine, Bioengineering Program, Division of Biological & Environmental Science & Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia.
Department of Biochemistry, Faculty of Science, University of Jeddah, Jeddah, Saudi Arabia.

Zainab N Khan (ZN)

Laboratory for Nanomedicine, Bioengineering Program, Division of Biological & Environmental Science & Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia.
Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia.
Red Sea Research Center (RSRC), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia.

Hepi H Susapto (HH)

Laboratory for Nanomedicine, Bioengineering Program, Division of Biological & Environmental Science & Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia.

Yanyan Li (Y)

Cell Migration and Signaling Laboratory, Bioscience Program, Division of Biological & Environmental Science & Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.

Yara Marghani (Y)

Laboratory for Nanomedicine, Bioengineering Program, Division of Biological & Environmental Science & Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia.
Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia.

Arwa A Alghuneim (AA)

Cell Migration and Signaling Laboratory, Bioscience Program, Division of Biological & Environmental Science & Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.

Rubén Díaz-Rúa (R)

Core Laboratories, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.

Sherin Abdelrahman (S)

Laboratory for Nanomedicine, Bioengineering Program, Division of Biological & Environmental Science & Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia.
Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia.

Shuroug Al-Bihani (S)

Core Laboratories, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.

Farid Ahmed (F)

Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
Center of Innovation in Personalized Medicine (CIPM), King Abdulaziz University, Jeddah, 21589, Saudi Arabia.

Raed I Felimban (RI)

Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
Center of Innovation in Personalized Medicine (CIPM), King Abdulaziz University, Jeddah, 21589, Saudi Arabia.

Heba Alkhatabi (H)

Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
Center of Innovation in Personalized Medicine (CIPM), King Abdulaziz University, Jeddah, 21589, Saudi Arabia.
Hematology Research Unit, King Fahd Medical Research Centre, King Abdulaziz University, Jeddah, 21589, Saudi Arabia.

Raed Alserihi (R)

Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
Center of Innovation in Personalized Medicine (CIPM), King Abdulaziz University, Jeddah, 21589, Saudi Arabia.

Malak Abedalthagafi (M)

Department of Pathology and Laboratory Medicine, Emory School of Medicine, Atlanta, USA.

AlShaibani AlFadel (A)

Division of Hematology, Stem Cell Transplantation & Cellular Therapy, Oncology Center, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.

Abdalla Awidi (A)

Cell Therapy Center, The University of Jordan, Amman, Jordan.
Medical School, The University of Jordan, Amman, Jordan.
Jordan University Hospital, Amman, Jordan.

Adeel Gulzar Chaudhary (AG)

Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
Center of Innovation in Personalized Medicine (CIPM), King Abdulaziz University, Jeddah, 21589, Saudi Arabia.

Jasmeen Merzaban (J)

Cell Migration and Signaling Laboratory, Bioscience Program, Division of Biological & Environmental Science & Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.

Charlotte A E Hauser (CAE)

Laboratory for Nanomedicine, Bioengineering Program, Division of Biological & Environmental Science & Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia. charlotte.hauser@kaust.edu.sa.
Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia. charlotte.hauser@kaust.edu.sa.
KAUST Smart Health Initiative (KSHI), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia. charlotte.hauser@kaust.edu.sa.
Red Sea Research Center (RSRC), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Saudi Arabia. charlotte.hauser@kaust.edu.sa.
ORCID: 0000-0001-8251-7246

Classifications MeSH