Alteration of long and short-term hematopoietic stem cell ratio causes myeloid-biased hematopoiesis

Katsuyuki Nishi, Taro Sakamaki, Akiomi Nagasaka, Kevin S. Kao, Kay Sadaoka, Masahide Asano, Nobuyuki Yamamoto, Akifumi Takaori-Kondo, Masanori Miyanishi

Preprint posted on 20 January 2024 https://www.biorxiv.org/content/10.1101/2024.01.18.576239v1.full

Long lifespan shortens short-term hematopoietic stem cell proportion. Nishi et al. show how the ratio between long-term and short-term hematopoietic stem cells changes with age and plays a role in myeloid-biased hematopoiesis.

Selected by Manuel Vicente, Anaisa Ferreira

Categories: cell biology, developmental biology, immunology

Background

Aging of the immune system is characterized by the decline of both innate and adaptive immunity. Impaired memory responses and thymic involution are examples of age-induced changes of adaptive immunity [1], while aging innate immune cells show defective phagocytic capacity and responsiveness [2]. This decrease in immune resilience is correlated with a higher incidence of infections, poorer responses to vaccination, and dysregulated systemic inflammation [3,4].

Hematopoiesis refers to the lifelong production of blood cells from hematopoietic stem cells (HSCs), which are self-renewing and multipotent. During aging, HSCs undergo functional decline and acquire a myeloid-bias in the bone-marrow [5,6]. This myeloid-bias of HSCs may underlie the immune dysfunction observed with aging. However, it is unknown if the age-dependent decline of the hematopoietic system can be attributed to HSC-intrinsic properties, or to a changing bone marrow microenvironment.

In this preprint, the authors aimed to study the mechanisms that promote the myeloid-bias of HSCs during aging. They evaluated HSC differentiation in the bone marrow and the mirroring changes in circulating immune cell frequencies. More specifically, a previously described reporter for long-term (LT)-HSCs and transplant assays were used to address hematopoiesis potential and lineage bias in young and aged mice.

Key findings

1. Aging does not affect long-term HSC lineage output

The HSC compartment can be divided in two populations, long-term (LT)-HSCs and short-term (ST)-HSCs, where the former has a higher self-renewal capacity than the latter. It was previously shown that the transplantation of aged bulk HSCs (both LT- and ST-HSCs) led to a myeloid-biased hematopoiesis in the recipient mice [7,8], potentially due to myeloid-prone HSCs accumulating with aging. To determine if the longer-lived LT-HSCs contribute to the aging-related myeloid-bias, the authors co-transplanted young (2-3 months) and aged (2 years) LT-HSCs into young recipients and evaluated the lineage proportions of different circulating immune cells. Bulk hematopoiesis from young LT-HSCs was predominant, whereas the lineage proportions derived from either young or aged LT-HSCs did not differ. Additionally, RNA-sequencing analysis of young and aged LT-HSCs showed similar myeloid and lymphoid signatures. Together, these results suggest that aging does not promote the accumulation of LT-HSC myeloid-biased clones.

2. Aging decreases the percentage of ST-HSCs, which is sufficient for peripheral myeloid-skewing

Having observed the maintenance of lineage output in aged LT-HSC, the authors suggested a role for ST-HSC in the observed myeloid bias. Three important observations were made:

(1) ST-HSCs lacked self-renewal capacity, as demonstrated by the null donor chimerism at the HSC compartment 12 months after transplantation;
(2) The ratio of LT-HSC to ST-HSC increased with age (information from the text, as data is in a supplementary figure not available in the preprint). Interestingly, when young mixed HSCs were transplanted at the ratios that mirror young (LT/ST of 2/8) or aged (LT/ST of 5/5) proportions, the aged ratio led to an increase in the myeloid-biased circulating percentages.
(3) Similar to LT-HSCs, RNA-sequencing analysis of young and aged ST-HSCs also revealed comparable myeloid and lymphoid expression signatures. Based on the observations above, the authors then concluded that the myeloid-bias of HSCs found during aging is due to the relative decrease of ST-HSCs.

3. Thymic involution and splenic suppression may exacerbate the aging peripheral myeloid-bias

The authors observed that the myeloid-biased hematopoiesis of aged mice was greater than the bias of animals transplanted with an aged LT- to ST-HSC ratio. Thus, the authors considered that, in addition to the LT- to ST-HSC ratio, other factors must contribute to observed myeloid bias. To address this, young LT-HSCs were transplanted into young or old recipients and hematopoietic reconstitution was examined. Curiously, a myeloid-bias in peripheral blood was observed in the aged recipients, in spite of a reduction of common myeloid progenitor percentages in the bone marrow, when compared to young recipients. This latter observation suggested extra-medullary origins of additional myeloid differentiation promoting factors. Indeed, donor-derived cell frequencies were reduced in spleens and thymi in aged recipients, when compared to young ones, suggesting impaired lymphocyte generation. The authors highlight these impairments as major extra-medullary factors for the promotion of hematopoietic myeloid-bias.

What we like about the preprint and why this new work is important

This preprint highlights a novel perspective in the study of the myeloid-bias hematopoiesis during aging. It cleverly uses a reporter model of LT- vs. ST-HSC identification and provides detailed experiments to isolate the dynamics and roles of these two cellular compartments. The work presented here provides a new aspect to consider in hematopoiesis of aged individuals: the ratio between LT- and ST-HSCs. In fact, the chronological alteration of this ratio (increasing with age) is shown here to influence myeloid-biased hematopoiesis.

Tags: hematopoiesis, hematopoietic stem cells

Posted on: 24 April 2024

doi: https://doi.org/10.1242/prelights.37184

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Author's response

Masanori Miyanishi shared

Previous work from the authors described the Hoxb5 reporter for the identification of LT-HSC (used here). The references regarding aging-mediated myeloid-skewing in hematopoiesis use different HSC identification strategies. A comparative analysis of LT/ST-HSC compositions of differently identified bulk HSCs is urgently needed in this field of research.

R: We utilized CD34 as one of the critical markers to define bulk HSCs. On the other hand, the CD48-based HSC definition is also widely employed. However, the CD48-defined HSC fraction contains a significant proportion of CD34-positive fractions, such as MPPs, which have little reconstitution ability after transplantation. Therefore, it is challenging to precisely assess the ratio change LT-HSC and ST-HSC. Even when employing Hoxb5, comparisons are drawn between LT-HSC and ST-HSC/MPP, potentially yielding disparate results from those presented here.

Is the increase in the LT- to ST-HSC ratio as a result of aging due to an accumulation of LTHSCs or due to a decrease in ST-HSC numbers?

R: As observed in previous reports, the total number of bulk HSCs significantly increased with age. Given that the number of LT-HSCs increases as well, we believe that the increase in the LT-HSC/ST-HSC ratio is primarily due to the increase in LT-HSC number.

What are the factors that promote the LT/ST-HSC ratio increase observed during aging? Do the authors propose a preponderance of cell-intrinsic or extrinsic mechanisms?

R: In addition to aging, external stimuli such as bone marrow suppression induced by irradiation and chemotherapy also lead to a similar phenomenon. The acceleration of this ratio change depending on the strength of hematopoietic requirements suggests that extrinsic mechanisms are predominant.

Are the young and aged LT/ST-HSC ratios maintained over time after transplantation, independently of the recipient mouse’s age?

R: As we addressed in Q3, the LT-HSC/ST-HSC ratio increases rapidly post-transplantation. While we have not conducted experiments specifically addressing whether this change is dependent or independent of the age of recipient mice, we anticipate similar alterations when aged mice are used as recipients.

Do different transplant LT/ST-HSC ratios influence the differentiation dynamics of LT-HSCs to ST-HSCs? Aged ST-HSCs do not repopulate the HSC compartment of recipient mice, but a transplant of mixed LT/ST-HSCs at the ratio of 2/8 and 5/5 did. It would be interesting to understand if the repopulation of ST-HSCs by LT-HSCs is compromised when the 5/5 ratio is used. These dynamics could be explored using the CD45.1/CD45.2 system to differentiate between transplanted ST-HSCs and newly differentiated ST-HSCs.

R: Compared to young ST-HSCs, hematopoietic repopulation is markedly reduced in aged ST-HSCs, likely due to further weakening of their self-renewal capacity with aging. On the other hand, we previously reported that ST-HSCs exhibit prolonged self-renewal and behave akin to LT-HSCs by increasing the number of supporting cells and decreasing the hematopoietic requirement per cell. Based on these findings, we believe that ST-HSCs can extend hematopoiesis by mixing with cells possessing robust self-renewal capacity such as LT-HSCs, even under conditions of strong hematopoietic requirement, which is not observed when only ST-HSCs are transplanted.

Other conditions have also been associated with increased myelopoiesis. Do you believe that an increase in LT/ST-HSC ratio could underlie an increase in myelopoiesis outside the scope of aging?

R: As mentioned in Q3, besides aging, the LT-HSC/ST-HSC ratio increases in response to strong hematopoietic requirements such as those induced by irradiation and chemotherapy.

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