New HSC Rejuvenation Strategy May Improve Bone Marrow Transplantation

Review of “Intercellular Transfer of Microvesicles from Young Mesenchymal Stromal Cells Rejuvenates Aged Murine Hematopoietic Stem Cells” from STEM CELLS by Stuart P. Atkinson

Over their relatively long lifetime, hematopoietic stem cells (HSCs) suffer from a barrage of stresses and strains, including DNA damage, replication stress, and ribosomal stress [1, 2], that culminate in the age-related loss of functionality. These deficiencies become problematic in the setting of bone marrow stem cell transplantation [3-5] and have led to the search for strategies to “rejuvenate” aged HSCs.

Now, new research from the laboratory of Vaijayanti P. Kale (National Centre for Cell Science, Pune, Maharashtra, India) has described a fascinating new approach to return lost functionality to aged mouse HSCs: the transfer of microvesicles (MVs) containing positive regulators of autophagy derived from young mesenchymal stem cells (MSCs) [6].

Kulkarni et al. discovered in their new study that:

• A 36-hour coculture of aged HSCs (from 18-24 month-old mice) with young MSCs (from 6-8 week-old mice) reversed signs of aging in HSCs
• The rejuvenation of aged HSCs occurred thanks to the intercellular transfer of large membrane-derived extracellular vesicles known as microvesicles (MVs) carrying autophagy-related mRNAs
• The process of autophagy degrades damaged organelles, cell membranes and proteins, and protects against the aging process
• While MVs from young MSCs promoted autophagy in aged HSCs, smaller membrane-derived extracellular vesicles known as exosomes carried microRNA species that inhibited autophagy
• Subsequent analysis of MSCs demonstrated that aged MSCs displayed high levels of activated Akt signaling when compared to young MSCs
• Elevated signaling correlated with a reduction in the levels of autophagy-related mRNAs in MVs and higher levels of autophagy-inhibiting miRNAs in exosomes
• This finding suggests the existence of a new niche-mediated mechanism of HSC aging involving MSCs
• Pharmacological inhibition of Akt in aged MSCs reversed age-related changes to MVs
• Reduced Akt signaling allowed “rescued” MSC-derived MVs to rejuvenate aged HSCs and boost their functionality in transplantation studies to a level higher than that observed for MVs from young MSCs

Can young MSCs or rescued MVs turn back the clock of aged HSCs and improve bone marrow stem cell transplants in human patients? Stay tuned to the Stem Cells Portal to find out!

Discussion Points

• What mechanism(s) cause elevated Akt signaling and differential miRNA partitioning during aging?
• What other signaling pathways are important to MSC-mediated HSC rejuvenation?
• Can this strategy be transferred to human patients requiring bone marrow stem cell transplants?

References

1. Beerman I, Seita J, Inlay MA, et al., Quiescent hematopoietic stem cells accumulate DNA damage during aging that is repaired upon entry into cell cycle. Cell Stem Cell 2014;15:37-50.
2. Flach J, Bakker ST, Mohrin M, et al., Replication stress is a potent driver of functional decline in ageing haematopoietic stem cells. Nature 2014;512:198-202.
3. Kollman C, Howe CW, Anasetti C, et al., Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. Blood 2001;98:2043-51.
4. Woolthuis CM, Mariani N, Verkaik-Schakel RN, et al., Aging impairs long-term hematopoietic regeneration after autologous stem cell transplantation. Biol Blood Marrow Transplant 2014;20:865-71.
5. Mehta J, Gordon LI, Tallman MS, et al., Does younger donor age affect the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies beneficially? Bone Marrow Transplant 2006;38:95-100.
6. Kulkarni R, Bajaj M, Ghode S, et al., Intercellular Transfer of Microvesicles from Young Mesenchymal Stromal Cells Rejuvenates Aged Murine Hematopoietic Stem Cells. STEM CELLS 2018;36:420-433.