Transplantation of Young Bone Marrow into Old Mice Produces Systemic Benefits

Researchers here report that transplanting bone marrow from young donor mice into old recipient mice produces a range of benefits, such as improvement in the behavior of macrophage cells. Bone marrow stem cells are responsible for producing blood and immune cells, among other important populations, and this capability is degraded in a number of ways with age. Introducing younger stem cells and their supporting structures is a plausible means to at least partially reverse this process. That said, this sort of approach is unlikely to arrive in human medicine in exactly the same form, given the challenges involved in bone marrow transplantation. It is not a procedure one would want to undergo unless there were no other options, and deploying it widely as a preventative therapy doesn't seem feasible in the present environment. The more likely outcome is for researchers to continue to work in mice so as to better identify specific mechanisms involved in bone marrow aging, those that might be manipulated with small molecule drugs, gene therapies, and the like.

The bone marrow is an important reservoir of stem cells and progenitor cells which cross-talk with peripheral organs to help maintain tissue function. Hematopoietic stem/progenitor cells (HSCs) are responsible for producing blood cells throughout life and these downstream cells play an active role in maintaining tissue homeostasis. With aging reduced function of bone marrow cells correlates with dysfunction of peripheral organs. For example, the decline in immune function with age, referred to as immunosenescence, contributes to the accumulation of senescent cells, persistent low grade inflammation, and reduced responses to injury. The bone marrow is also an important source of endothelial progenitor cells (EPCs) which participate in the generation and repair of vasculature endothelium; aging leads to a decline in circulating EPC number and function.

Different strategies have been proposed to rejuvenate the aged bone marrow such as pharmacological treatments, gene therapy, and dietary interventions. However, most approaches have focused on the effect of rejuvenation on HSC differentiation and EPC colony formation rather than effects on peripheral tissues. Therefore, we hypothesized that reconstituting aged mice with young bone marrow leads to stable engraftment of young cells in aged mice and rejuvenates tissue repair responses.

We recently utilized this bone marrow rejuvenation approach to study the effect aging has on the repair processes initiated post-myocardial infarction. Aged mice were reconstituted with young Sca-1+ bone marrow stem cells and examined 4 months later to allow cross talk between the bone marrow and heart. Young bone marrow reconstitution rejuvenated cardiac endothelial cells which contributed to improved repair and better outcome following myocardial infarction. In addition to improved angiogenesis, our lab has shown that rejuvenation using reconstitution of young cells improves multiple repair processes. Young bone marrow cell transplantation increases the proliferation of resident cardiac cells, increases epicardial derived cell migration/activation, and enhances the acute inflammatory response following myocardial infarction in aged mice.

Beyond cardiac repair, we have shown that bone marrow cells interact with other tissues and that bone marrow rejuvenation can benefit multiple organ systems. Reconstituting aged mice with young cells leads to the repopulation of the retina with young bone marrow derived microglia. Within the retina these cells secrete cytoprotective factors such as fibroblast growth factor-2 and insulin-like growth factor-1 which limit cell death following ischemia/reperfusion injury. More recently, we also demonstrated that bone marrow rejuvenation leads to the introduction of young bone marrow-derived microglia in the brain and that these cells act to improve learning and memory responses compared with mice receiving old bone marrow. Mechanistically, young bone marrow-derived microglia adopt a neutral or anti-inflammatory phenotype while old bone marrow-derived microglia adopt a pro-inflammatory phenotype. These results are consistent with studies which have linked increased neuroinflammation to a decline in cognitive function.

Link: https://doi.org/10.18632/aging.102838

Comments

With the dawn of gene therapy in genetic blood diseases like sickle cell and hemophilia there is now a lot of work to get rid of stem cell therapy with chemo and radiation, if that problem is solved all you have to do is to select stem cells that are youthful, with falling sequencing prices that should be feasible, even for those stem cell clinics that are popping up everywhere right now and sell only BS as far as I can tell.

Posted by: Tom at February 14th, 2020 1:50 PM

The authors of the article forgot to mention the work of Russian authors from 12 April 2019 | https://doi.org/10.3389/fgene.2019.00310
Extension of Maximal Lifespan and High Bone Marrow Chimerism After Nonmyeloablative Syngeneic Transplantation of Bone Marrow From Young to Old Mice. by Marina V. Kovina et al.
The goal of that work was to determine the effect of nonablative syngeneic transplantation of young bone marrow (BM) to laboratory animals (mice) of advanced age upon maximum duration of their lifespan. To do this, transplantation of 100 million nucleated cells from BM of young syngeneic donors to an old nonablated animal was performed at the time when half of the population had already died. As a result, the maximum lifespan (MLS) increased by 28 ± 5%, and the survival time from the beginning of the experiment increased 2.8 ± 0.3-fold. The chimerism of the BM 6 months after the transplantation was 28%.

Posted by: Dmitry Dzhagarov at February 14th, 2020 10:44 PM

Recently, methods have appeared (so far only for mice) to obtain hematopoietic cells from iPSCs, which makes it possible to transplant recipients of their own bone marrow cells rejuvenated through iPSCs. (eg. Generation of hematopoietic cells from mouse pluripotent stem cells in a 3D culture system of self-assembling peptide hydrogel https://doi.org/10.1002/jcp.29110)
Current bone marrow (BM) or hematopoietic stem cell (HSC) transplantations require recipient conditioning that is accompanied by significant adverse effects in patients. Engineered bone tissues could potentially be used as ectopic BM surrogates.
see also. : In vivo engineering of bone tissues with hematopoietic functions and mixed chimerism
https://doi.org/10.1073/pnas.1702576114 and
Injectable, scalable 3D tissue-engineered model of marrow hematopoiesis https://doi.org/10.1016/j.biomaterials.2019.119665

Posted by: Dmitry Dzhagarov at February 15th, 2020 1:46 AM

Who says it's all that hard to insert young human bone marrow into old bones (like mine)? Maybe nanomachines could do it, or long needles, or all kinds of harmless infective agents. Almost certainly the only reason why it's an ordeal NOW is because it's such a rare procedure. Thus no-one has searched for an alternative way to implant this valuable bone marrow where it's needed.

Posted by: Zan at February 16th, 2020 10:18 AM

Pretty brutal Dmitry; those 'donor' young mice were killed, their bones cleaned of muscle and then crushed for donation, and this was repeated 6 times for a single old mice. I trust the equivalent human procedure will be a little more humane!

Interestingly Zan, there seems no need to inject the donor bone marrow into YOUR bones. An intravenous injection is all that's required for (some of those) cells to find their way to the bone marrow and begin to take it over.

Posted by: Mark at February 17th, 2020 5:24 AM

The problem with bone marrow ablation is that it is a very nasty, invasive and risky procedure. Without ablation, you have a mix. If we find a way to do gradual/staged ablation the risks will be greatly reduced. That of course brings the usual conclusion that more research is needed.

I can imagine growing compatible stem cells for replacement. Nothing new here. The next stage is to make those SC resistant to some chemo drug and once there is some chymerism to start introducing it locally to the bone marrow in high doses. That would allow for gradual and much safer transition.

Posted by: cuberat at February 17th, 2020 7:19 AM

Increasing chimerism shows that there is no need for ablation Cuberat. The next step is ex vivo expansion of autologous stem cells (probably using ROCK inhibitors) and telomerase activation, before re-implantation.

Posted by: Mark at February 17th, 2020 8:03 AM

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