Format

Send to

Choose Destination
Nat Biotechnol. 2019 Mar;37(3):293-302. doi: 10.1038/s41587-019-0017-2. Epub 2019 Feb 11.

An injectable bone marrow-like scaffold enhances T cell immunity after hematopoietic stem cell transplantation.

Shah NJ1,2,3,4,5, Mao AS1,2, Shih TY1,2, Kerr MD1,2,5, Sharda A3,4,6, Raimondo TM1,2, Weaver JC2, Vrbanac VD7,8, Deruaz M7,8, Tager AM7,8, Mooney DJ9,10, Scadden DT11,12,13,14.

Author information

1
John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA.
2
Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA, USA.
3
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
4
Harvard Stem Cell Institute, Cambridge, MA, USA.
5
Department of Nanoengineering, University of California, San Diego, La Jolla, CA, USA.
6
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA.
7
Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
8
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
9
John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA. mooneyd@seas.harvard.edu.
10
Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, MA, USA. mooneyd@seas.harvard.edu.
11
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA. dscadden@mgh.harvard.edu.
12
Harvard Stem Cell Institute, Cambridge, MA, USA. dscadden@mgh.harvard.edu.
13
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA. dscadden@mgh.harvard.edu.
14
Cancer Center, Massachusetts General Hospital, Boston, MA, USA. dscadden@mgh.harvard.edu.

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for multiple disorders, but deficiency and dysregulation of T cells limit its utility. Here we report a biomaterial-based scaffold that mimics features of T cell lymphopoiesis in the bone marrow. The bone marrow cryogel (BMC) releases bone morphogenetic protein-2 to recruit stromal cells and presents the Notch ligand Delta-like ligand-4 to facilitate T cell lineage specification of mouse and human hematopoietic progenitor cells. BMCs subcutaneously injected in mice at the time of HSCT enhanced T cell progenitor seeding of the thymus, T cell neogenesis and diversification of the T cell receptor repertoire. Peripheral T cell reconstitution increased ~6-fold in mouse HSCT and ~2-fold in human xenogeneic HSCT. Furthermore, BMCs promoted donor CD4+ regulatory T cell generation and improved survival after allogeneic HSCT. In comparison to adoptive transfer of T cell progenitors, BMCs increased donor chimerism, T cell generation and antigen-specific T cell responses to vaccination. BMCs may provide an off-the-shelf approach for enhancing T cell regeneration and mitigating graft-versus-host disease in HSCT.

PMID:
30742125
PMCID:
PMC6636841
DOI:
10.1038/s41587-019-0017-2
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center