Extracellular vesicles from bone marrow mesenchymal stromal cells of severe aplastic anemia patients attenuate hematopoietic functions of CD34⁺ hematopoietic stem and progenitor cells

Abstract

Mesenchymal stromal cells (MSC) regulate hematopoiesis in the bone marrow (BM) niche and extracellular vesicles (EVs) released by BM-MSC are important mediators of the cross-talk between BM-MSC and hematopoietic stem and progenitor cells (HSPC). We have previously demonstrated that BM-MSC of severe aplastic anemia (SAA) patients have an altered expression of hematopoiesis regulatory molecules. In the present study, we observed that CD34 + HSPC when cocultured with BM-MSC EVs from aplastic anemia patients exhibited a significant reduction in colony-forming units (p = .001), cell proliferation (p = .002), and increased apoptosis (p > .001) when compared to coculture with BM-MSC EVs from controls. Collectively, our results highlight that EVs derived from the BM-MSC of SAA patients impair the hematopoiesis supporting function of HSPC.

Altered Expression of microRNAs Implicated in Hematopoietic Dysfunction in the Extracellular Vesicles of Bone Marrow-Mesenchymal Stromal Cells in Aplastic Anemia

“…Additionally, pathways analysis showed enrichment of several pathways such as apoptosis, MAPK, PI3K/Akt, mTOR, chemokine receptor signalling, etc., which are crucial for maintaining hematopoietic homeostasis 42 . Our findings here provide with an insight that miRNAs enriched in AA BM-MSC EVs could potentially dampen HSPC functions in the microenvironment through impediment of these pathways, which is in alignment with our previous finding where we showed that AA BM-MSC EVs promoted apoptosis in healthy HSPC 25 . Concomitantly, our in-silico analysis of miRNA-mRNA interaction revealed that these EV miRNAs targeted 235 HSPC genes and their pathways analysis showed significant enrichment of pathways involved in cell survival and cell death.…”

“…BM-MSC are the key cells of the BM microenvironment that supports HSPC functions by direct cell contact and paracrine release of growth factors and EVs 5,6,13–16 . We have previously demonstrated that BM-MSC EVs from AA patients hamper the proliferative, colony-forming capacity and enhance apoptosis of HSPC 25 . However, the exact mechanism by which AA BM-MSC EVs exert their functional effect on HSPC is unclear.…”

“…However, studies investigating the role of BM-MSC EVs in AA are scarce. It has been shown that BM-MSC EVs from AA patients induced apoptosis and reduced the cellular proliferation and colony forming ability of HSPC 25 . Another study has shown that EVs from healthy BM-MSC potentially ameliorate bone marrow failure symptoms in the murine AA model 36 .…”

“…We have recently reported that BM-MSC EVs from AA patients can inhibit the proliferative and colony-forming ability of HSPC by enhancing apoptosis, thus highlighting the altered hematopoiesis supporting properties of AA BM-MSC EVs 25 . Mechanistically, EVs can profoundly alter the target cell phenotype by altering gene expression and associated pathways by releasing bioactive factors such as miRNAs encapsulated within them 17 .…”

TERC haploid cell reprogramming: a novel therapeutic strategy for aplastic anemia

“…MSCs can effectively regulate hematopoiesis, particularly in preventing the replacement of BM hematopoietic cells by adipocytes in patients with AA. MSCs also improve the hematopoietic microenvironment, and promote BM hematopoiesis; therefore, maintenance of a normal number and optimal activity of MSCs is essential for the recovery of hematopoietic function (Srivastava et al 2022 ).…”