Diminished Immune Cell Adhesion in Hypoimmune ICAM-1 Knockout Pluripotent Stem Cells

Area of Science:

• Regenerative Medicine
• Immunology
• Gene Editing

Background:

• Hypoimmune gene edited human pluripotent stem cells (hPSCs) show promise for cell therapies by evading immune rejection.
• Current strategies primarily target adaptive immunity, neglecting innate immune cells involved in early graft rejection.
• The adhesion molecule ICAM-1 plays a key role in both adaptive and innate immune responses post-transplantation.

Purpose of the Study:

• To investigate ICAM-1 as a novel target for enhancing hypoimmune strategies in hPSCs.
• To evaluate the impact of ICAM-1 knockout (KO) on immune cell binding and graft rejection.
• To assess the efficacy of combining ICAM-1 KO with existing hypoimmune edits.

Main Methods:

• Utilized CRISPR/Cas9 gene editing to knock out ICAM-1 in hPSCs.
• Assessed immune cell binding to ICAM-1 KO hPSC-derived therapies in vitro.
• Evaluated T cell proliferation responses in vitro.
• Tested in vivo graft retention and protection in NeoThy humanized mice.
• Introduced ICAM-1 KO into first-generation hypoimmune hPSCs.

Main Results:

• ICAM-1 KO significantly diminished binding of multiple immune cell types to hPSC-derived therapies.
• ICAM-1 KO resulted in reduced T cell proliferation in vitro.
• ICAM-1 KO grafts showed enhanced in vivo retention and protection against immune cell attack in humanized mice.
• Combining ICAM-1 KO with existing hypoimmune edits further improved immune evasion.

Conclusions:

• ICAM-1 is a viable target for developing advanced hypoimmune stem cell therapies.
• ICAM-1 KO enhances the hypoimmune capacity of hPSCs, reducing both innate and adaptive immune responses.
• This strategy holds potential for improving the efficacy and safety of regenerative medicine for various diseases, including cardiovascular pathologies.