Rectification of radiotherapy-induced cognitive impairments in aged mice by reconstituted Sca-1+ stem cells from young donors

Abstract

Background: Radiotherapy is widely used and effective for treating brain tumours, but inevitably impairs cognition as it arrests cellular processes important for learning and memory. This is particularly evident in the aged brain with limited regenerative capacity, where radiation produces irreparable neuronal damage and activation of neighbouring microglia. The latter is responsible for increased neuronal death and contributes to cognitive decline after treatment. To date, there are few effective means to prevent cognitive deficits after radiotherapy.Methods: Here we implanted hematopoietic stem cells (HSCs) from young or old (2-or 18-month-old, respectively) donor mice expressing green fluorescent protein (GFP) into old recipients and assessed cognitive abilities 3 months post-reconstitution.Results: Regardless of donor age, GFP + cells homed to the brain of old recipients and expressed the macrophage/ microglial marker, Iba1. However, only young cells attenuated deficits in novel object recognition and spatial memory and learning in old mice post-irradiation. Mechanistically, old recipients that received young HSCs, but not old, displayed significantly greater dendritic spine density and long-term potentiation (LTP) in CA1 neurons of the hippocampus. Lastly, we found that GFP + /Iba1 + cells from young and old donors were differentially polarized to an anti-and pro-inflammatory phenotype and produced neuroprotective factors and reactive nitrogen species in vivo, respectively. Conclusion: Our results suggest aged peripherally derived microglia-like cells may exacerbate cognitive impairments after radiotherapy, whereas young microglia-like cells are polarized to a reparative phenotype in the irradiated brain, particularly in neural circuits associated with rewards, learning, and memory. These findings present a proof-of-principle for effectively reinstating central cognitive function of irradiated brains with peripheral stem cells from young donor bone marrow.

Delineating the relationship between immune system aging and myogenesis in muscle repair

“…The studies described above demonstrate that aging alters the skeletal muscle microenvironment, resulting in unfavorable tissue repair; however, using various approaches, rejuvenation of old satellite cell function is feasible. The bone marrow (BM) is reservoir of stem/progenitor cells, which we have shown to communicate with peripheral tissues to alter tissue repair (Li et al., 2013; Tobin et al., 2017; Wlodarek et al., 2020). Based on these studies, we investigated how BM aging affects the satellite cell population during rest and after acute injury in young vs old mice or after BM chimeras with young or old Sca‐1 + cells into old mice.…”

Considering Cause and Effect of Immune Cell Aging on Cardiac Repair after Myocardial Infarction

“…Heterochronic (young to old) bone marrow transplant in 20-22 month old mice improves angiogenesis via upregulation of Cxcl12, Vegf and the inflammatory response post-MI [172,174,208]. Young bone marrow cell transplantation can also improve cognitive function and muscle repair in aged mice, implying a greater scope for bone marrow cell aging on systemic tissue aging [209][210][211]. Of note, cognitive improvements in old mice with young bone marrow is caused by changes in both neurons and microglia, the immune cell population in the brain [209,212].…”

“…Young bone marrow cell transplantation can also improve cognitive function and muscle repair in aged mice, implying a greater scope for bone marrow cell aging on systemic tissue aging [209][210][211]. Of note, cognitive improvements in old mice with young bone marrow is caused by changes in both neurons and microglia, the immune cell population in the brain [209,212]. Targeting circulating immunological factors which correlate with age and negatively influence cognition, such as β-2-microglobulin or Ccl11 [213,214] have been proposed to be putative targets that may limit age-associated disease.…”

Home Away From Home: Bioengineering Advancements to Mimic the Developmental and Adult Stem Cell Niche

“…Depletion of factors that sustain the stem cell niche has been increasingly recognized to promote aging (Carlson and Conboy, 2007), tissue deterioration, and cancer (Rossi et al, 2008). This is evidenced by a large body of work, showing that heterochronic parabiosis and transplantation can promote the regenerative capacity of aged stem cell populations when put in a "young" niche (Conboy et al, 2005;Rebo et al, 2016;Poulos et al, 2017;Wlodarek et al, 2020). As such, it is critical to develop in vitro model systems that allow controlled insight into the parameters that govern stem cell survival, self-renewal, and differentiation.…”