Reconceptualizing Aplastic Anemia—Seed, Worm, Soil

ABSTRACT

Background

Aplastic anemia (AA) encompasses a group of hematological syndromes often misdiagnosed, resulting in a decrease in the overall blood cell count and representing a form of bone marrow failure. The disease is defined by damage to hematopoietic stem cells due to various physical, chemical, and biological factors. The diagnosis of the disease is based on clinical presentation, as the underlying etiology remains poorly understood, which complicates treatment options. Understanding bone marrow failure disorders began with cytomorphological studies, which led to the identification of AA syndrome based on the shared characteristics of pancytopenia and bone marrow failure. However, the pathological mechanisms underlying these conditions remain complex and confusing. A comprehensive analysis of biological characteristics, clinical regression, and therapeutic responses was subsequently conducted. This multifaceted approach employed various diagnostic techniques, including immunology, histochemistry, molecular genetics, and second‐generation sequencing, to progressively elucidate the underlying syndrome of AA and clarify the disease classification. Consequently, there is a pressing need to adopt a new conceptual framework for understanding AA.

Objective

To clarify the definition, characteristics, diagnostic basis and existing problems of AA, and to put forward the necessity of establishing a new conceptual framework for understanding AA.

Methods

This review reinterpret AA based on the “seed, worm, and soil” doctrine.

Conclusion

Research advancements have gradually clarified the mechanistic understanding of AA. The disease has evolved from a “hybrid” entity, characterized by disparate elements, to a more analytically recognized condition. We anticipate comprehensive investigations into its characteristics, ultimately enhancing treatment efficacy through precision medicine.

Aplastic anemia (AA) encompasses a group of hematological syndromes often misdiagnosed, resulting in a decrease in the overall blood cell count and representing a form of bone marrow failure. We reinterpret AA based on the “seed, worm, and soil” doctrine. We anticipate comprehensive investigations into its characteristics, including the discovery of previously unidentified ailments, the identification of novel diagnostic markers, and the development of more effective targeted therapies, ultimately enhancing treatment efficacy through precision medicine.

1. Introduction

Aplastic anemia (AA) is a rare bone marrow failure disorder, with a high mortality rate if untreated [1, 2]. The definition and diagnosis of AA have evolved over time, forming a more independent and precise disease classification system through ongoing research [1, 3]. Dr. Paul Ehrlich first introduced the concept, which was expanded upon by Dr. Anatole Chauffard in 1904. AA encompasses a group of bone marrow hematopoietic failure syndromes caused by various physical, chemical, and other etiological factors. The primary symptoms include decreased bone marrow hematopoietic cell proliferation and reduced peripheral blood plasma cells. Western scholars grouped similar syndromes under “AA syndromes”, speculating they might originate from “seed, worm, and soil abnormalities” [4, 5]. In the early to mid‐20th century, it was recognized that children with AA often had organ developmental abnormalities, leading to the concept of “congenital AA”. This was based on reports of congenital dyskeratosis [6], Fanconi anemia [7], Diamond‐Blackfan anemia [8], and Shwachman‐Diamond syndrome [9]. Over the last 50 years, the understanding of AA has been refined to a narrower definition: “T‐cell hyperimmune bone marrow failure”, focusing on biological features, genetic traits, clinical progression, and therapeutic response. Recent advancements in cytology, immunology, genetics, and molecular biology have deepened our understanding of AA. This review will reinterpret AA based on the “seed, worm, and soil” doctrine (Figure 1).

FIGURE 1.

The “seed, worm, soil” theory of aplastic anemia.

2. A New Conceptualization of the Term “Seed”

The initial understanding of AA's etiology was based on the observed reduction in the number of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPC) due to direct toxic effects resulting from exposure to various antigens (Figure 2). These antigens include industrial exposures, including benzene [10, 11, 12], as well as pharmaceutical agents, such as chloramphenicol and anti‐epileptic drugs [13, 14, 15, 16]. Pregnancy is also a notable antigenic exposure [17]. This view was revised in the late 1960s by Mathé et al. [18], who first hypothesized the immunological basis of AA's pathogenesis. In patients with AA, the bone marrow shows a scarcity of myeloid precursors for erythrocytes, granulocytes, and platelets, with very few differentiated pluripotent cells. Detection of CD34⁺ cells via flow cytometry [19] is nearly impossible. The ability to transiently restore hematopoiesis through immunosuppression suggests that HSCs persist in patients with AA, albeit in a quiescent state [20]. T cells from patients with AA can induce apoptosis in HSCs through a human leukocyte antigen‐DR (HLA‐DR)‐restricted process, specifically via the Fas/FasL pathway, leading to the death of bone marrow HSCs/HPCs [21, 22, 23]. The expression of HLA‐DR and Fas increases as stem cells mature. Therefore, primitive HSCs rarely express HLA or Fas, indicating that most AA attacks are actually targeted at more mature HSCs [24, 25].

FIGURE 2.

The pathogenesis of AA is closely linked to abnormalities in hematopoietic stem cells. Among these factors, antigen exposure, somatic mutations, and telomere shortening can lead to HSC abnormalities. Current treatment options for HSC in patients with AA are based on HSC transplantation.

The introduction of targeted next‐generation sequencing (NGS) has revealed that somatic mutations play a major role in the clonal hematopoiesis (CH) [26, 27] seen in AA. Genomic studies show that 71%–80% of patients with AA exhibit CH, with somatic mutations becoming more prevalent with age [26, 28, 29]. The most frequently identified mutations include PIGA, BCOR, BCORL1, DNMT3A, and ASXL1. PIGA, crucial for synthesizing the glycosylphosphatidylinositol anchor protein, is often used to diagnose paroxysmal nocturnal hemoglobinuria (PNH). The detection rate is approximately 60% [30, 31]. In AA, PIGA mutations are detected in approximately 7.5%–40% of patients with AA; however, up to 68% present with PNH clones upon diagnosis, and 19% progress directly to AA‐PNH syndrome [26, 28, 32, 33]. These distinct mutations are often closely linked to progression‐free survival (PFS) and overall survival (OS) in patients with AA. Studies have confirmed that PIGA and BCOR/BCORL1 mutations are associated with favorable responses to immunotherapy, suggesting a better prognosis. Conversely, patients with AA who have DNMT3A, ASXL1, or other specific mutations tend to have poorer treatment outcomes and a higher risk of progression to myelodysplastic syndrome or acute myeloid leukemia (MDS/AML) [26, 34]. Furthermore, 17% of patients with AA develop HLA class I allele deletions [29]. Advances in detection technology have clarified the mechanisms behind these deletions, particularly neutral copy number deletions in chromosome 6 short‐arm heterozygotes (6pCN‐LOH) and loss‐of‐function mutations in pathogenic HLA class I risk alleles, which are key features of immune‐mediated bone marrow failure [35, 36]. Preliminary single‐cell RNA sequencing results from our group showed that human endogenous retroviruses (HERVs) are up‐regulated in HSPCs of AA, and that reactivation of HERVs may affect the transcriptional landscapes of HSPCs, as well as energy metabolism and biosynthesis, and hypothesized that HERVs may be the initiating antigens for triggering AA [37].

Telomere shortening, often detected in patients with AA, indicates the presence of a progenitor cell defect [38, 39]. Conversely, leukocyte telomere length can indicate increased lymphocyte activation and exacerbation of autoimmune diseases [40]. Shorter telomeres are significantly linked to higher risks of disease progression, lower survival rates, increased relapse susceptibility, and the development of new clones in AA. Mutations in TERC, TERT, and DKC1—commonly associated with bone marrow failure—are strongly correlated with telomere shortening in AA [40, 41, 42].

Despite being generally regarded as a benign condition, AA is prone to transformation into other bone marrow failure disorders over time. Around 15% of patients with advanced AA may develop MDS, AML, or both—a process known as “clonal evolution”. This is marked by the appearance of somatic mutations and genetic changes [34]. About 65% of patients with MDS secondary to AA exhibit somatic mutations, with high‐risk mutations in ASXL1, RUNX1, and splicing factor genes. However, common AA mutations, including PIGA, HLA, BCOR/BCORL1, and DNMT3A, generally lack the potential to induce progression to secondary MDS. Regarding genetic changes, chromosome 7 deletions (del(7q)) occur in 20%–60% of patients with AA and secondary MDS. Unlike del(7q) linked to TP53 mutations and complex karyotypes in primary MDS, del(7q) in secondary MDS is often associated with RUNX1 and ASXL1 [26, 43, 44, 45]. Additionally, AA is prone to developing PNH following immunosuppressive therapy (IST), such as antithymocyte globulin/Antilymphocyte Globulin (ATG/ALG) with cyclosporine A. A meta‐analysis of 15 studies involving 1349 patients found that individuals with a pre‐treatment PNH clone‐positive status had improved hematological responses to intensive IST (IIST). However, they were more likely to develop PNH or AA‐PNH syndrome following IIST [46].

Advancements in diagnostic and therapeutic techniques have enhanced our understanding of clonal transformation in AA. In clinical practice, it is not uncommon to encounter a cohort of patients with AA who do not meet the diagnostic criteria for any known allopathic cytopenic disorders and do not present with conditions such as MDS, PNH, or AML. However, these patients may exhibit CH or clonal evolution. Many patients with cytopenias also fail to meet the diagnostic criteria for recognized allopathic cytopenic disorders and can only be classified under immune‐related hematocellular reduction. To diagnose and categorize these patients, recent concepts such as clonal hematopoiesis of indeterminate potential (CHIP), isolated cytopenia of undetermined significance (ICUS), and clonal cytopenia of undetermined significance (CCUS) have been proposed, as they are considered hematological preneoplastic states. The CHIP concept was first defined in 2015 by Steensma et al. [47]. Patients with CHIP must have a mutant allele score of ≥ 2% in peripheral blood and must not meet the diagnostic criteria for malignancy or exhibit morphological abnormalities in blood cells. Those with CHIP typically experience longer survival and a lower conversion rate to AML compared to patients with MDS. The most frequently identified candidate driver mutations are in genes such as DNMT3A, TET2, and ASXL1. However, this pathological hematopoietic process may occasionally lead to the development of MDS or AML in patients with CHIP [47, 48]. The concept of idiopathic cytopenias of undetermined significance (ICUS) was first defined in 2007 to describe unexplained hematopenia that does not meet the diagnostic criteria for MDS [49]. Subsequently, the concept of CCUS was proposed for patients with ICUS who have one or more somatic mutations [50]. The clinical course of CCUS resembles that of patients with low‐risk MDS. A study [51] revealed that approximately 10% of patients with ICUS developed a WHO‐classified myeloid tumor within 5 years, whereas over 75% of patients with CCUS experienced tumor progression within the same timeframe. This indicates a higher risk of progression for CCUS than for ICUS. Current evidence suggests that CHIP or AA with clonal hematopoiesis and MDS may represent different stages in the malignant transformation of hematopoietic clones, as evidenced by an increase in the number of driver mutations and mutant alleles observed from CH in AA to MDS/AML [52] (Figure 3).

FIGURE 3.

Schematic representation of benign and malignant bone marrow failure.

Currently, transplantation remains a crucial option for treating patients with AA, addressing the underlying “seed” causative factor. In children and adolescents, survival rates after transplantation from tissue‐compatible sibling donors reach 80%–90% [53, 54]. However, the potential for transplantation is often limited by a lack of suitable donors, the risk of graft rejection, and the occurrence of acute and chronic graft‐versus‐host disease (GvHD), along with other complications. Additionally, umbilical cord transplants are utilized for AA, primarily in pediatric patients, with an efficacy rate of up to 90%. Despite this, several limitations persist [55, 56]. Stem cell stimulation is also being explored as a treatment for AA, with eltrombopag demonstrating effects on BMSCs, particularly through increasing the number of HSC/HPC and CD34⁺ cells in the bone marrow. This may enhance hematopoiesis across all three lineages [57, 58].

3. A New Conceptualization of the Term “Worm”

As mentioned, the hematopoietic damage leading to AA is primarily driven by an antigen‐induced immune response, making immune system irregularities significant contributors to the disease's development. At the same time, we have reason to believe that immune factors are the most critical pathogenic factors in acquired AA, meaning that the “worms” are the most important.

The concept of AA autoimmunity was first validated by R. Hoffman and colleagues in 1977, who provided experimental evidence indicating that lymphocytes from patients with AA could suppress erythropoiesis in vitro [59]. Subsequent studies have consistently shown that exposure to specific antigens can trigger the polyclonal expansion of CD4⁺ T lymphocytes [60, 61] and oligoclonal expansion of cytotoxic CD8⁺ T lymphocytes [22]. This expansion results in the overproduction of inhibitory lymphokines, including interferon (IFN)‐γ and tumor necrosis factor‐α. These cytokines can exert direct toxic effects on CD34⁺ cells and upregulate Fas expression on these cells, leading to apoptosis of bone marrow precursor cells through the Fas/FasL pathway [23, 62, 63]. CD8⁺ T lymphocytes, as a crucial T cell subset, exhibit abnormal activation characterized by effector phenotype expansion and excessive activation of cytotoxic pathways. Through dual mechanisms of direct killing and inflammatory cytokine release, they induce increased apoptosis and suppressed proliferation/differentiation of HSPCs, ultimately leading to bone marrow failure—the core pathogenesis of acquired acute AA [64, 65]. Abnormal CD8⁺ T cell activation originates from antigen presentation and clonal expansion of the T cell receptor (TCR) [66]. Various in vivo and in vitro factors can trigger antigenic epitope changes on HSPC surfaces. Activated by antigen‐presenting cells such as dendritic cells (DCs), naive CD8⁺ T cells differentiate into cytotoxic T cells expressing activation markers like HLA‐DR⁺, CD28⁺, and CD57⁺, infiltrating the bone marrow in large numbers and establishing clonal dominance [66, 67, 68]. These cells directly lyse HSPCs by releasing granzyme B and perforin, while simultaneously secreting large amounts of Th1‐type inflammatory cytokines such as IFN‐γ and TNF‐α. This activates apoptotic signaling pathways within hematopoietic cells and suppresses the expression of hematopoietic growth factor receptors, further exacerbating hematopoietic suppression [66]. Moreover, these factors positively feedback to activate more CD8⁺ T cells, forming an immune damage amplification loop. It has been established that counts of hematopoietic progenitor and CD34⁺ cells are markedly diminished in patients with AA. In contrast to the prevailing myeloid deficiencies affecting granulocytes, erythrocytes, and megakaryocytes, lymphocyte counts remain within the normal range, and the functionality of B cells and T cells is typically unimpaired [20, 69]. Additionally, an imbalance in the ratio of regulatory T cells (Tregs) to T helper (Th17) cells influences the autoimmune response [70, 71]. Several studies [70, 72, 73] have reported an increase in Th17 cells and a significant reduction in Treg cells in bone marrow and peripheral blood samples from patients with AA. However, when treatment is effective, the number of Th17 cells stabilizes at levels comparable to those in healthy individuals, while Treg cell counts return to their normal range. Naïve CD4⁺ T lymphocytes act as precursor cells that differentiate into two distinct pathways, influenced by tumor growth factor (TGF)‐β [74, 75, 76]. Among these, Treg cells play a crucial role in maintaining immune homeostasis, whereas Th17 cells are associated with autoimmune responses and inflammation [72, 77, 78]. Bone marrow mesenchymal stromal cells (BMMSCs) significantly influence the Th17/Treg imbalance observed in patients with AA, as will be discussed in the following section. The early administration of anti‐IL‐17 antibodies [72] and the mechanism involving the STAT3/HIF‐1α/RORγt pathway [78] appear to have a beneficial therapeutic impact on restoring this imbalance.

Furthermore, the role of DCs in the pathogenesis of AA should not be overlooked [79]. Studies have shown that in patients with severe aplastic anemia (SAA), an elevated ratio of myeloid dendritic cells (mDCs) to plasmacytoid dendritic cells (pDCs) enhances antigen presentation and T‐cell activation. This results in a bias in the Th1/Th2 ratio favoring Th1 and an imbalance between Th1/Th2 and Th17/Treg [80, 81, 82] ratios. Concurrently, the increased phagocytic activity of mDCs in patients with SAA leads to aberrant activation of cytotoxic T lymphocytes (CTLs), ultimately resulting in decreased levels of hemoglobin (HB), platelets (PLT), white blood cells (WBC), and reticulocytes [83, 84]. Recent research has also indicated that elevated HLA‐DQ expression in mDCs and reduced CTLA‐4 expression on Tregs in patients with AA—who often achieve significant remission following IST—may support the hypothesis that these factors are critical mechanisms contributing to the pathogenesis of AA [85]. Moreover, the hyperfunction of DCs has been shown to correlate with alterations in the levels of cofilin [85], glucose‐6‐phosphate dehydrogenase [86], pyruvate kinase M2 (PKM2) [87], and profilin1 [81]. These changes contribute to T‐cell hyperfunction and are significant drivers of AA.

Innate immunity also plays a role in the pathogenesis of AA. Patients with SAA exhibit a marked reduction in the proportion of natural killer (NK) cells, while IST has proven effective in restoring the number of NK cells [21, 88]. Additionally, the expression of CD158a, NKG2D, and NKp46 on NK cells was found to be elevated in patients with SAA compared to normal controls. This suggests that the T‐cell hyperfunction associated with SAA‐related hematopoietic failure may be closely linked to the high expression levels of total NK cells, as well as specific subpopulations, including CD56^Bright and CD56^dimNK cells, along with NKp46 and perforin on NK cells [88].

In conclusion, the immune damage in AA is significantly driven by the oligoclonal expansion of CD8⁺ T lymphocytes, the hyperfunction of Th1 cells, the overactivation of mDC, and the enhanced inflammatory effects of Th17 cells. This is compounded by the diminished function of Tregs and CD56^bright NK cells.

Increased understanding of AA, coupled with the advent of novel therapeutic modalities, particularly the ongoing refinement of immune‐targeted therapies, has made it possible to induce tumors as a result of radiotherapy, targeted therapy, cellular therapy, and autoimmune‐mediated damage. Recognizing this critical aspect of the disease's progression has led to more aggressive and targeted treatment approaches for affected patients. A 2021 study by Ruan et al. [89] included 25 patients with different tumors who were confirmed to have AA following a median radiotherapy dose of 45 Gy across an average of three chemotherapy cycles. The results indicated that cyclosporine A, at concentrations of 100–200 ng/mL, effectively treated this patient cohort, achieving a complete remission rate (CRR) of 36% (9/25) and a partial remission rate (PRR) of 44% (11/25), leading to an overall remission rate (ORR) of 80% (20/25) by the end of the follow‐up period. In a retrospective analysis by Chi et al. in 2023 [90], avatriptopa was found to yield ORRs of 32.4%, 55.9%, and 58.8% at months 1, 3, and 6, respectively, with CRRs of 5.9%, 14.7%, and 23.5% during the same time frame. The median time to respond was 3 months (range 1–6), indicating a favorable therapeutic outcome. Furthermore, IST has been shown to be an effective treatment option for AA, particularly in cases that arise following radiotherapy for malignancy. This conclusion was reached by Noriharu Nakagawa and colleagues in 2021 [91], suggesting that IST should be the preferred treatment for patients with AA who have developed the condition following radiotherapy for malignancy. The optimal outcomes are likely to be achieved when the solid tumor is in a state of CR.

Furthermore, the chimeric antigen receptor T‐cell (CAR‐T) regimen offers a novel therapeutic avenue in clinical practice, particularly for relapsed or refractory Burkitt lymphoma and leukemia. However, it can also lead to secondary AA. Recent studies have highlighted the efficacy of CAR‐T therapy in patients with AA secondary to relapsed or refractory Burkitt lymphoma [92]. Despite its benefits, CAR‐T therapy has been associated with the development of secondary AA. In this context, thrombopoietin receptor agonists have shown promise in treating acquired AA following anti‐CD19‐CAR‐T therapy [93, 94].

4. A New Conceptualization of the Term “Soil”

Approximately 70% of the pathogenesis in patients with AA is attributed to immune‐mediated processes. While immunotherapy has shown benefits for these patients, about 30% continue to experience refractory or relapsing crises. This suggests that the heterogeneity of the hematopoietic microenvironment may also play a significant role in the pathogenesis of AA and could represent a potential target for therapeutic intervention [95] (Figure 4).

FIGURE 4.

Immunological factors and abnormalities in the hematopoietic microenvironment have been implicated in the pathogenesis of AA.

The bone marrow microenvironment serves as the foundation for the generation of healthy HSCs and HPCs [96, 97]. It consists primarily of bone marrow stromal cells, extracellular matrix components, and a local cytokine gradient, all of which influence the survival, differentiation, and self‐renewal of hematopoietic stem cells [1]. MSCs, in particular, have garnered extensive research interest due to their remarkable differentiation potential, self‐renewal capacity, and immunosuppressive properties [98, 99]. They primarily function through paracrine secretion, while their progeny—including adipocytes, osteoblasts, and reticulocytes—play a significant role in the bone marrow ecological niche. These cells can interfere with hematopoiesis and modulate immune responses [100]. Additionally, MSC‐derived exosomes have the potential to partially replicate the immunomodulatory functions of MSCs [98, 101, 102]. However, patients with AA exhibit abnormal bone marrow characteristics [103], with BMMSCs showing abnormal morphology, increased apoptosis, and reduced proliferation. These cells also demonstrate a tendency towards osteogenic differentiation and a tendency to differentiate into adipocytes [104, 105, 106]. Some studies have shown that arsenic trioxide can inhibit the lipogenic differentiation of BMSCs in patients with AA while promoting their osteogenic differentiation. Additionally, down‐regulation of miR‐204 has been implicated in the regulation of BMSC differentiation [107]. Transcriptomic analyses indicate that cells from patients with AA exhibit aberrant gene expression at all stages of cell proliferation, apoptosis, cycling, and chemotaxis compared to normal controls [108, 109]. Furthermore, acquired AA is closely associated with abnormalities in both the number and functionality of MSCs. Exosomes derived from AA‐MSCs (AA‐Exos) contribute to immune dysregulation by impairing the immunosuppressive effects on T cells [110]. As previously mentioned, an imbalance in the Th17/Treg ratio is evident in patients with AA. The corrective effect of bone marrow‐derived mesenchymal stromal cell‐derived exosomes (BMMSC‐Exos) on this imbalance has been demonstrated. The principal mechanism may be associated with the partial transfer of miR‐23a‐3p, leading to the inhibition of IL‐6 expression [111] alongside SphK1‐mediated enrichment of exosomal sphingosine 1‐phosphate (S1P) [112]. These findings provide novel insights into potential therapeutic avenues. In SAA MSCs, the inhibitory effect on CD4⁺ T lymphocytes differentiating into Th17 cells was diminished, resulting in the generation of dysfunctional Treg cells. Concurrently, elevated levels of IL‐17 and IL‐1β, along with reduced levels of TGF‐β, confirmed the presence of an inflammatory milieu that was overproduced in SAA MMSCs. This ultimately contributed to the lack of immunoprotection observed in the bone marrow MSCs of patients with AA [113]. Additionally, BMMSCs from patients with AA exhibit an increased senescence phenotype, the mechanism of which has been demonstrated to be closely associated with DNA damage and telomere shortening [114]. Nevertheless, the roles of osteoblasts and osteoclasts in AA bone marrow remain to be investigated, and they are postulated to represent a promising avenue for future research into the treatment of patients with AA.

The therapeutic concept for AA is founded on the understanding that abnormalities in HSCs and the immune system contribute to the disease's development. However, the toxicity and high relapse rates associated with IST [115, 116, 117], along with the multifactorial limitations of Allo‐HSCT, have led to a re‐evaluation of treatment options for AA. In this context, the infusion of allogeneic BMMSCs has emerged as a promising clinical treatment option. Significant advancements have been made in understanding the mechanisms by which BMMSCs exert their regulatory effects. Studies indicate that in patients with chronic AA, BMMSCs modulate Th17/Treg homeostasis mainly through the Notch/RBP‐J/FOXP3/RORγt pathway [118]. Nevertheless, the efficacy of BMMSC infusion alone is less than 30% [119, 120]. Consequently, current research emphasizes enhancing the efficacy of BMMSCs after infusion, particularly by optimizing their homing efficiency to target sites in patients with AA. Several studies have demonstrated that following BMMSC infusion, these cells can be detected in various organs, including the spleen and skin, rather than being restricted to the bone marrow [121, 122, 123]. For instance, Chen et al. confirmed that lentivirus‐transfected CXCR4‐BMSCs exhibited enhanced migration efficiency to the bone marrow via the SDF‐1/CXCR4 axis when infused into mice with bone marrow failure [124]. Haploidentical hematopoietic stem cell transplantation (haplo‐HSCT) is frequently associated with an increased risk of graft failure and severe GvHD. In a study conducted by Wang et al. [125], it was observed that the co‐transplantation of culture‐expanded donor‐sourced BMMSCs into children with SAA undergoing haplo‐HSCT without an HLA‐identical sibling donor resulted in a reduction of GvHD. Furthermore, a combination of HLA haplo‐HSCT and the infusion of allogeneic BMMSCs has been shown to be an effective treatment for SAA in children and adolescents, with an OS rate of 87.15% ± 3.3% after a median follow‐up of 40 months, as reported by Li et al. [126]. The 2022 study also revealed that the co‐transplantation of HLA haplotype‐conjugated HSCs, along with umbilical cord‐derived MSCs (UC‐MSCs), represents a safe and effective treatment strategy for SAA in adults [127]. Conversely, several studies, supported by systematic evaluations and meta‐analyses, have indicated that prophylactic infusion of BMMSCs in patients with SAA undergoing haplo‐HSCT is not an optimal approach. These studies found no significant differences in the incidence of acute and chronic GvHD, 2‐year OS, or cytomegalovirus infection rates [128].

Concurrently, extensive research is being conducted on the metabolic and aging factors associated with hematopoietic diseases, such as AA. The mechanism of action is predominantly linked to HSCs and HPCs. Aging involves functional changes that organisms must undergo to survive, while senescence is defined as an irreversible form of cell cycle arrest caused by intra‐ and extracellular damage, including oxidative stress, DNA damage, and metabolic dysfunction [129, 130, 131, 132, 133]. Senescence reduces the regenerative capacity of HSCs and skews their differentiation towards the medullary lineage. To elucidate the relationship between HSC senescence and BMMSCs, Singh et al. [134] demonstrated that the overexpression of CXCR4 on senescent BMMSCs results in functional deficits in HSCs and HPCs, as shown in a mouse model of senescence. Furthermore, age‐associated hematopoietic dysfunction may be addressed through interventions targeting the stromal cell‐derived factor‐1 (SDF‐1)/CXCR4 axis. A 2020 study using isotope‐labelled relative and absolute quantitative (iTRAQ) proteomics analysis identified mRNA shearing as a significant contributor to HSC senescence. This analysis highlighted a series of genes commonly associated with mRNA shearing, such as Sf3b1 and U2AF1, as well as less‐studied genes, including Rbmxl1, Dhx16, Pcbp2, Pabpc1, which are also involved in this process [135]. Additionally, Poisa‐Beiro et al. discovered that glucose metabolism may influence the aging process of HSCs and (HPCs) [136]. These findings enhance the theoretical framework for understanding the pathogenesis of AA and generate new hypotheses for potential therapeutic interventions.

5. Conclusion

In conclusion, research advancements have gradually clarified the mechanistic understanding of AA. This includes distinguishing between AA and immune‐related pathologies, addressing PNH associated with HSC abnormalities, as well as MDS and congenital bone marrow failure syndromes, such as ICUS and CCUS. The disease has evolved from a “hybrid” entity, characterized by disparate elements, to a more analytically recognized condition. Moving forward, we anticipate comprehensive investigations into its characteristics, including the discovery of previously unidentified ailments, the identification of novel diagnostic markers, and the development of more effective targeted therapies, ultimately enhancing treatment efficacy through precision medicine.

Author Contributions

X.X.: conceptualization, writing – review and editing, project administration. Z.W., J.H.: writing – original draft, visualization, resources. C.L., R.F.: supervision, funding acquisition, project administration. All authors contributed to the article and approved the submitted version.

Funding

This work was supported by the Key research and development projects of the Ministry of Science and Technology (grant no. 2024YFC2510500), the National Natural Science Foundation Project (grant no. 82470141, 82270142, 82300239), the Tianjin Municipal Natural Science Foundation (grant no. 24ZGSSSS00050), the Tianjin Science and Technology Planning Project (grant no. 24ZXGZSY00090), the Tianjin Municipal Health Commission Project (grant no. TJWJ2023XK003), and the Tianjin Medical University Climbing Program Talent Project.

Ethics Statement

The authors have nothing to report.

Consent

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.