The novel function of latexin in hematopoiesis was originally identified by the natural variation of HSC number among different mouse strains . Latexin acts endogenously in HSCs to negatively regulate their population size by enhancing apoptosis and by decreasing self-renewal. Latexin, a 222 amino acid protein, was first discovered in the developing rat brain as a marker of the specification of discrete brain regions . Latexin is the only known naturally occurring caroboxypeptidase inhibitor in mammals , but bears no structural similarities to other members, thus representing a heretofore unknown family of carboxypeptidase inhibitors. It specifically inhibits the A/B, but not N/E, family of metallocarboxypeptidases . Latexin has been crystalized  and the 3-dimensional structure, association with its natural substrate, human carboxypepetidase A (Cpa), has been solved . Interestingly, although the latexin gene sequence shows no homology with any previously reported genes, it does contain two cystatin-like motifs with a substrate-binding cleft in the middle. Cystatins function as cysteine peptidase inhibitors in the lysosomal autophagic pathway . Therefore, latexin may have important functions in protein turnover and trafficking. Moreover, latexin expression is significantly induced by lipopolysaccharide in mast cells, indicating its potential role in inflammation . A recent article suggests that latexin is a biomarker for canine blood-derived M1 and M2 macrophages [9▪]. Although accumulating evidence indicates the multifaceted functions of latexin in different types of cells, its regulatory role in HSC and hematopoiesis remains largely unknown. In this review, we will summarize the cellular and molecular mechanisms by which latexin regulates HSC self-renewal and regeneration under homeostatic and stress conditions. We will explore its potential role in human hematopoiesis and therapeutic implication in stem cell transplantation.
LATEXIN IN HEMATOPOIESIS
Latexin in physiological hematopoiesis
Hematopoietic stem cells are key for the sustained production of mature and functional blood cells. They have the unique ability to perpetuate themselves through self-renewal and to replenish dying or damaged cells through multilineage differentiation. The balance between self-renewal and differentiation is critical for homeostatic hematopoiesis. A disrupted balance could lead to serious problems such as blood dysplasia or malignancy [10▪▪]. The flexibility of HSCs to adapt to physiological needs and in response to stress or injury is achieved by the precise regulation of many molecules and signaling pathways [11▪,12]. However, identification of the collection of genes contributing to critical stem cell functions is far from complete.
HSC number and function demonstrate natural variation among humans as well as among different mouse strains [13–16]. The natural variation is largely attributed to DNA variants in the genome that function as regulatory elements to control gene expression [17▪▪]. The genetic diversity is a powerful but underused tool for unraveling the critical gene networks in stem cell regulation. Using genome-wide association studies, increasing numbers of genetic variants have been strongly implicated in hematologic phenotypes and diseases in humans [17▪▪,18,19]. Recently, several reports have revealed the important role of genetic variants in regulating epigenetics [20–24]. DNA variations affect chromatin structure and transcription factor binding, thus collectively lead to differential gene expression and phenotypic diversity in a population.
Inbred mouse strains provide a model system for exploring the myriad of regulatory gene combinations contributing to hematologic diversity [18,25]. We and others carried out a comparative study of two inbred strains, C57BL/6 (B6) and DBA/2 (D2), in which large natural variations in a number of stem cell traits were identified [13–16]. One of the most significant traits is the natural size of the HSC population; that is, young B6 mice have three-fold to eight-fold fewer stem cells in bone marrow than D2 mice, depending on the assay used for stem cell quantification. We further identified latexin as an underlying regulatory gene whose expression is negatively correlated with HSC number [1,26].
To further understand the specific function of latexin in hematopoiesis, we generated a mouse model with depletion of latexin gene in vivo [27▪]. Latexin inactivation increases the number of HSCs, hematopoietic progenitor cells (HPCs) and differentiated blood cells. The expansion of the entire hematopoietic system is controlled within the physiological range of variation, suggesting the unique feature of latexin as a genetic factor in regulating HSC and hematopoiesis. The expanded HSCs maintain their long-term repopulation capacity and balanced lineage differentiation upon transplantation. Latexin depletion intrinsically increases the self-renewal and survival of HSCs but does not affect proliferation and cycling. With aging, latexin knockout mice did not develop leukemia, lymphoma and other malignancies, and their health condition is comparable with the age-matched control mice. These findings suggest that loss or antagonism of latexin function can lead to the controlled expansion of HSCs and HPCs without exhaustion and risk of malignant hyperplasia.
Latexin in stress hematopoiesis
Hematopoietic system has very high turnover rate, thus is very sensitive to replicative stress. Indeed, radiation and chemotherapeutic drugs induce acute myelosuppression with the rapid loss of blood cells, leading to significantly increased risk for infection and hemorrhage in patients. The treatment could also cause long-term HSC damage, which may lead to the development of leukemia or dysplasia years after treatment. Therefore, protection of normal tissues, especially stem cells, from radiotherapy-induced and chemotherapy-induced damages will ultimately benefit patients receiving these treatments.
As latexin depletion enhances HSC functionality in the physiological condition, we asked how these cells respond to different types of stress. We challenged latexin-depleted mice with 5-fluorouracil, a chemotherapeutic drug for cancer treatment, and found that their blood cell counts recover faster, HPC population are better preserved, and HSCs maintain higher self-renewal capacity (unpublished data) [27▪]. Moreover, our published work has shown that latexin sensitizes HPCs to radiation-induced cell death, suggesting its potential role in radiation response . Therefore, we hypothesize that latexin inhibition not only protects chemotherapy-induced acute myelosuppression and long-term HSC damages but also may mitigate radiation-associated hematopoietic toxicity. In addition, our unpublished work shows that latexin-depleted HSCs can reconstitute the hematopoietic system during several rounds of serial transplantation without exhaustion, suggesting that they have better tolerance to replicative stress without functional impairment. Altogether, loss of latexin seems to confer HSCs with a higher endurance to genotoxic and cytotoxic stresses with maintenance of regeneration capability.
Latexin in malignant hematopoiesis
We and others have found that latexin is downregulated or absent in a variety of types of solid and liquid tumors because of promotor hypermethylation [29▪,30,31–36]. Overexpression of latexin suppresses tumor cell growth, indicating its potential tumor suppressor function. A recent report also suggests that the decreased level of latexin in bone microenvironment confers cancer cells chemoresistance [37▪]. However, latexin knockout mice at a young age did not have apparent hematologic malignancies, nor did they with aging or stress conditions. These findings suggest that latexin may function differently in tumors that are complicated by different oncogenic signals. Therefore, the role of latexin in tumorigenesis needs further investigation.
LATEXIN SIGNALING IN HEMATOPOIESIS
Latexin and thrombospondin 1
The molecular mechanisms by which latexin regulates HSC function remain largely unknown. We recently identified thrombospondin 1 (Thbs1) as a downstream target that mediates latexin function [27▪]. Latexin deletion decreases expression and secretion of Thbs1 in HSCs. Thbs1 is a multidomain adhesive glycoprotein that mediates cell–cell and cell–matrix communication. On the basis of our and others’ reports, we propose that Thbs1 mediates the function of latexin in HSCs through several signaling pathways . In normal conditions, decreased expression of Thbs1 reduces apoptosis via down-regulation of active caspase 3, thus enhancing survival of latexin-depleted HSCs. Downregulation of Thbs1 may also change the interaction of stem cells with the microenvironment, which affects self-renewal, mobilization, and/or homing. Involvement of latexin in cell-niche communication has been found by other groups [34,39]. In stress conditions, it is reported that absence of Thbs1 confers cells nearly complete resistance to high-dose radiation . Moreover, Thbs1 knockout mice demonstrated an accelerated hematopoietic recovery following 5-fluorouracil-induced myelosuppression . We observed the similar stress-tolerance phenotypes in latexin-depleted HSCs. In hematologic malignancies, Thbs1 has been shown to be downregulated in leukemia cells because of promoter hypermethylation, and enforced expression leads to tumor cell death , and these are consistent with what we and others found about latexin in cancer cells. Altogether, this evidence strongly supports the signaling cascade from latexin to Thbs1 in the regulation of HSC function in steady state, in response to stress, and in cancer development.
Latexin and carboxypeptidase A
It remains unclear how latexin transcriptionally regulates Thbs1. Latexin is primarily located in the cytoplasm, and it also may be present in the nucleus [8,43]. No evidence has shown that latexin acts as a transcription factor by directly interacting with DNA. Thus the involvement of latexin in gene transcription may be through its binding partners. Carboxypeptidase A is the canonical latexin-binding protein [6,8,44]. Whether the mechanism of action of latexin in HSCs is through this canonical pathway or not remains largely unknown. We have predicted several amino acids in latexin that may be involved in its binding to Cpa, including V161, H185, Q190, and E191. We are currently making mutants for these residues to determine whether they can interfere with the binding of latexin to Cpa, whether they will block the function of latexin in HSCs, and whether they can alter Thbs1 expression.
Latexin and ribosomal protein subunit 3
In additional to the canonical CPA pathway, we recently identified that ribosomal protein subunit 3 (Rps3) as a novel latexin-binding protein . Rps3 participates in ribosome assembly and protein synthesis. It has many important extraribosomal activities that may mediate the regulation of latexin in HSCs and hematopoiesis (Fig. 1).
Rps3 has been reported to facilitate spindle formation and chromosome movement during mitosis . Rps3 also has the endonuclease activity and is involved in DNA damage repair [46–48]. We found that latexin inhibits Rps3 from entering the nucleus upon irradiation, which in turn interferes with mitotic spindle formation, leading to cell cycle arrest, chromosomal abnormality, and cell death . Therefore, we speculate that deletion of latexin in HSCs will stimulate Rps3 nuclear translocation in which it can repair DNA damages, maintain genomic stability, and enhance cell survival, ultimately conferring radiation resistance.
It is reported that Rps3 binds to the p65 subunit of NF-kB complex and enhances its nuclear translocation [49,50]. Rps3 directs the NF-kB complex to specific target genes and activates or suppresses their transcription. Thbs1 promoter has NF-kB binding motif . We, therefore, hypothesize that deletion of latexin inhibits transcription of Thbs1, perhaps via the Rps3-NF-kB pathway.
Rps3 has been shown to bind p53 and Mdm2, thereby preventing p53 from Mdm2-mediated ubiquitination [52,53]. Our unpublished work shows that loss of latexin enhances the basal p53 protein level in steady state. This finding is consistent with the literature in which the basal p53 level has dynamic changes in nonstressed conditions, but such changes are insufficient for the activation of p53 target genes [52,54–56]. Instead, a low or basal level of p53 protects cells from accumulation of reactive oxygen species (ROS), and enhances the survival and repair of moderate damage [57,58]. It is possible that latexin deficiency causes unengaged Rps3 to remain free to bind and block Mdm2 and/or p53, leading to the p53 accumulation . As a result, lack of latexin enhances functional fitness (self-renewal) and survival of HSCs, perhaps by lowering ROS levels and reducing DNA damages. Altogether, understanding how latexin regulates HSC function either via canonical Cpa or noncanonical Rps3 pathway will advance our knowledge of HSC biology.
Latexin and slit homolog 2 protein precursor
Our original work identified three genomic loci that contribute to natural variations of HSC function . Latexin is one of them that is located in chromosome 3. Our laboratory recently identified another genetic factor on chromosome 5, slit homolog 2 protein precursor (Slit2), as a positive regulator of HSC number and function . Therefore, the function of Slit2 and latexin in HSCs seems to counteract each other to maintain homeostatic hematopoiesis. Very interestingly, it was reported that Slit2 protects intestinal stem cells from radiation-induced toxicity , which is opposite to the role of latexin in HSCs. This information suggests that natural genetic factors, such as latexin, Slit2, and perhaps other unidentified novel genes, may coordinately regulate HSC function in physiological and stress conditions (Fig. 2). Although there is a lack of evidence suggesting an interaction between latexin and Slit2, a recent study showed that latexin is co-localized with the Slit2 receptor, Robo4, in HSCs, and latexin ablation reduces the abundance of Robo4 . We speculate that loss of latexin expands the HSC population, and HSCs in turn down-regulate Robo4 expression and decease HSC numbers. If this hypothesis can be experimentally proven, it highly underscores the importance and power of the genetic diversity approach in uncovering novel regulatory networks in stem cell function.
LATEXIN IN HUMAN HEMATOPOIESIS
Natural genetic variation is associated with a variety of hematologic phenotypes in humans. Genome-wide association studies have revealed DNA variants that are implicated in hematologic traits such as fetal hemoglobin levels, hematocrit, cell counts, and sizes of different types of blood cells, as well as in disease susceptibility . However, very few genes underlying the vast majority of these DNA variants have been uncovered and very little is known about how they contribute to the phenotypic diversity in the population . As latexin is identified by the genetic diversity that arises through natural selection, it may play a similar role in other natural populations, such as humans. In fact, our unpublished data have indicated a negative correlation between latexin level and the number of HSCs and HPCs in healthy humans. Therefore, latexin may be involved in human hematopoiesis. A recent report has shown that a single-nucleotide polymorphism (SNP), rs6441224, in latexin promoter is associated with its expression level . It would be interesting to investigate whether latexin level and/or SNPs could be used as a biomarker to predict HSC population size in humans. The information could be useful for screening transplantation donors with a larger stem cell reservoir or for prediction of better recovery of cancer patients with radiation and chemotherapy. In addition, pharmaceutical intervention or genetic inactivation, either transiently or for extended periods, in the function and abundance of latexin may provide clinical opportunities for the expansion of stem cells and for mitigation of cancer therapy-associated toxicity. Therefore, understanding the role of latexin in human hematopoiesis will produce significant translational implications and impacts.
Latexin regulates hematopoiesis by increasing the self-renewal and survival of HSCs, leading to the expansion of HSC and HPC population and increased blood cell output. Latexin inactivation mitigates stress-induced HSC toxicity and myelosuppression. The mechanism of action of latexin in HSCs may be via the canonical Cpa and/or noncanonical Rps3-signaling pathways. Latexin may be involved in the regulation of human hematopoiesis. Therefore, latexin represents an important therapeutic target for HSC expansion in stem cell transplantation, and for mitigation of cancer therapy-induced normal tissue injury.
The authors wish to extend their apologies to our colleagues whose work we were unable to cite because of space limitations. We thank the Markey Cancer Center's Research Communications Office for editing and graphics support.
Financial support and sponsorship
The authors are supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under awards R01HL124015(Y.L.), R21HL140213 (Y.L.), UKY-CCTS UL1TR001998 (UKY-CCTS pilot), and the Markey Cancer Center's Biostatistics and Bioinformatics Shared Resource Facility as well as the Flow Cytometry Shared Resource Facility (P30CA177558).
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
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- ▪ of special interest
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