Hematopoietic rejuvenation strategies targeting niche signals in aging and response to cytotoxic conditioning
| Approach . | Method . | Outcome . | Age, mo . | Reference . |
|---|---|---|---|---|
| Aging: supplementation | ||||
| Insulin-like growth factor 1 | Ex vivo treatment, 100 ng/mL, 7 d | Improved B- and T-cell lineage output | 14 | 79 |
| Recombinant netrin-1 | In vivo, 40 μg/mL, 10 subcutaneous injections in 14 d | Restored DNA damage response on BM niche cells, fourfold increase in functional HSCs, improved engraftment efficiency, and reverted myeloid skewing | 18 | 101 |
| Thrombin-cleaved osteopontin | Ex vivo treatment, 40 ng/mL, 16 h | Improved B- and T-cell lineage output | 20-24 | 88 |
| Fecal microbiota suspension from young mice | In vivo, oral gavage, daily for 4 wk | Improved lymphopoiesis and lymphoid/myeloid differentiation | 20-24 | 104 |
| ADRβ3 agonist (BRL37344) | In vivo delivery with osmotic pump, 12 wk | Reverted donor chimerism and multilineage reconstitution | 20-24 | 95 |
| Young EC | 4-d infusion | Improved engraftment and lymphoid differentiation after whole BM transplantation | 24 | 99 |
| Aging: inhibition | ||||
| TGFbR1 inhibitor (SB-525334) | In vivo, 30 mg/kg, oral gavage, daily for 12 d | Reverted HSC expansion and restored lineage output | 24 | 102 |
| IL-1ra inhibitor (anakinra) | In vivo, 37 ug per mouse, IP injection, daily for 21 d | Improved lymphopoiesis and restored myeloid lineage output | 24 | 103 |
| IL-1ra inhibitor (anakinra) | In vivo, 10 mg/kg, IP injection, daily for 14 d | Improved B- and erythroid-cell recovery after 5-FU | 18-31 | 91 |
| Antibiotic treatment | 8 wk, metronidazole, ampicillin, and vancomycin at 1 mg/mL, neomycin trisulfate 0.5 mg/mL | Improved lymphopoiesis and lymphoid/myeloid differentiation | 24 | 103 |
| Cytotoxic conditioning: supplementation | Stress | |||
| EGF | In vivo, 0.5 mg/kg, daily, 4 doses | Accelerated hematopoietic regeneration, induces cycling, and increased SLAM KSL numbers | 5-FU | 105 |
| IL-1β | In vivo, 0.5 ug per mouse, IP injection, daily | Accelerated regenerative myelopoiesis | 5-FU | 106 |
| G-CSF | In vivo, 5 ug per mouse, IP injection, daily | Time point–dependent acceleration/extension of cGMP formation | 5-FU | 106 |
| Angiopoietin 1 | Adenoviral vectors | Stimulates hematopoiesis, shortened duration of 5-FU induced neutropenia | 5-FU | 107 |
| VEGF-A | Adenoviral vectors | Supports vascular regeneration | 5-FU | 107 |
| VEGF-A | In vivo, 2 μg per mouse per dose, 4 doses IV injection | Supports vascular regeneration and hematopoietic reconstitution, improved overall survival | 9 Gy | 74 |
| 4-MC | In vivo, 10 μg/kg, IP injection, daily for 7 wk | Restoration of HSC frequencies and hematopoietic regeneration | Cisplatin | 108 |
| Isolated and in vitro expanded ILC2 | In vivo, 2 × 105 cells per mouse per dose, 2 doses, IV | Accelerated hematopoietic recovery | 5-FU | 109 |
| Cytotoxic conditioning: inhibition | ||||
| Anti–TGF-β neutralizing antibody (1D11) | In vivo, 10 mg/kg, IP injection, 3 doses | Accelerated regeneration after 5-FU | 5-FU | 110 |
| Anti-NRP1 antibody | In vivo, 10 μg/kg, IP injection, 5 doses | Accelerates vascular remodeling and hematopoietic reconstitution | TBI (5Gy) 5-FU | 111 |
| PAI-1 inhibitor (TM5614) | In vivo, oral gavage, daily for 14 d | Improved hematopoietic regeneration after 5-FU | 5-FU | 112 |
| Approach . | Method . | Outcome . | Age, mo . | Reference . |
|---|---|---|---|---|
| Aging: supplementation | ||||
| Insulin-like growth factor 1 | Ex vivo treatment, 100 ng/mL, 7 d | Improved B- and T-cell lineage output | 14 | 79 |
| Recombinant netrin-1 | In vivo, 40 μg/mL, 10 subcutaneous injections in 14 d | Restored DNA damage response on BM niche cells, fourfold increase in functional HSCs, improved engraftment efficiency, and reverted myeloid skewing | 18 | 101 |
| Thrombin-cleaved osteopontin | Ex vivo treatment, 40 ng/mL, 16 h | Improved B- and T-cell lineage output | 20-24 | 88 |
| Fecal microbiota suspension from young mice | In vivo, oral gavage, daily for 4 wk | Improved lymphopoiesis and lymphoid/myeloid differentiation | 20-24 | 104 |
| ADRβ3 agonist (BRL37344) | In vivo delivery with osmotic pump, 12 wk | Reverted donor chimerism and multilineage reconstitution | 20-24 | 95 |
| Young EC | 4-d infusion | Improved engraftment and lymphoid differentiation after whole BM transplantation | 24 | 99 |
| Aging: inhibition | ||||
| TGFbR1 inhibitor (SB-525334) | In vivo, 30 mg/kg, oral gavage, daily for 12 d | Reverted HSC expansion and restored lineage output | 24 | 102 |
| IL-1ra inhibitor (anakinra) | In vivo, 37 ug per mouse, IP injection, daily for 21 d | Improved lymphopoiesis and restored myeloid lineage output | 24 | 103 |
| IL-1ra inhibitor (anakinra) | In vivo, 10 mg/kg, IP injection, daily for 14 d | Improved B- and erythroid-cell recovery after 5-FU | 18-31 | 91 |
| Antibiotic treatment | 8 wk, metronidazole, ampicillin, and vancomycin at 1 mg/mL, neomycin trisulfate 0.5 mg/mL | Improved lymphopoiesis and lymphoid/myeloid differentiation | 24 | 103 |
| Cytotoxic conditioning: supplementation | Stress | |||
| EGF | In vivo, 0.5 mg/kg, daily, 4 doses | Accelerated hematopoietic regeneration, induces cycling, and increased SLAM KSL numbers | 5-FU | 105 |
| IL-1β | In vivo, 0.5 ug per mouse, IP injection, daily | Accelerated regenerative myelopoiesis | 5-FU | 106 |
| G-CSF | In vivo, 5 ug per mouse, IP injection, daily | Time point–dependent acceleration/extension of cGMP formation | 5-FU | 106 |
| Angiopoietin 1 | Adenoviral vectors | Stimulates hematopoiesis, shortened duration of 5-FU induced neutropenia | 5-FU | 107 |
| VEGF-A | Adenoviral vectors | Supports vascular regeneration | 5-FU | 107 |
| VEGF-A | In vivo, 2 μg per mouse per dose, 4 doses IV injection | Supports vascular regeneration and hematopoietic reconstitution, improved overall survival | 9 Gy | 74 |
| 4-MC | In vivo, 10 μg/kg, IP injection, daily for 7 wk | Restoration of HSC frequencies and hematopoietic regeneration | Cisplatin | 108 |
| Isolated and in vitro expanded ILC2 | In vivo, 2 × 105 cells per mouse per dose, 2 doses, IV | Accelerated hematopoietic recovery | 5-FU | 109 |
| Cytotoxic conditioning: inhibition | ||||
| Anti–TGF-β neutralizing antibody (1D11) | In vivo, 10 mg/kg, IP injection, 3 doses | Accelerated regeneration after 5-FU | 5-FU | 110 |
| Anti-NRP1 antibody | In vivo, 10 μg/kg, IP injection, 5 doses | Accelerates vascular remodeling and hematopoietic reconstitution | TBI (5Gy) 5-FU | 111 |
| PAI-1 inhibitor (TM5614) | In vivo, oral gavage, daily for 14 d | Improved hematopoietic regeneration after 5-FU | 5-FU | 112 |
4-MC, 4-methylcatechol; cGMP, compact granulocyte/macrophage progenitor cluster; EGF, epidermal growth factor; G-CSF, granulocyte colony stimulating factor 3; IL-1ra, interleukin 1 receptor antagonist; KSL, cKit+Sca1+Lin−; SLAM, signaling lymphocytic activation molecule (CD150+CD48−); TGFbR1, transforming growth factor β receptor 1.