Multifaceted characterization of the signatures and efficacy of mesenchymal stem/stromal cells in acquired aplastic anemia

Abstract

Background: Longitudinal studies have verified the pivotal role of mesenchymal stem/stromal cells (MSCs) in the bone marrow microenvironment for hematopoiesis and coordinate contribution to leukemia pathogenesis. However, the precise characteristics and alternation of MSCs during acquired aplastic anemia (AA) remain obscure. Methods: In this study, we originally collected samples from both healthy donors (HD) and AA patients to dissect the hematological changes. To systematically evaluate the biological defects of AA-derived MSCs (AA-MSCs), we analyzed alterations in cellular morphology, immunophenotype, multi-lineage differentiation, cell migration, cellular apoptosis, and chromosome karyocyte, together with the immunosuppressive effect on the activation and differentiation of lymphocytes. With the aid of whole genome sequencing and bioinformatic analysis, we try to compare the differences between AA-MSCs and HD-derived MSCs (HD-MSCs) upon the molecular genetics, especially the immune-associated gene expression pattern. In addition, the efficacy of umbilical cord-derived MSC (UC-MSC) transplantation on AA mice was evaluated by utilizing survivorship curve, histologic sections, and blood cell analyses. Results: In coincidence with the current reports, AA patients showed abnormal subsets of lymphocytes and higher contents of proinflammatory cytokines. Although with similar immunophenotype and chromosome karyotype to HD-MSCs, AA-MSCs showed distinguishable morphology and multiple distinct characteristics including genetic properties. In addition, the immunosuppressive effect on lymphocytes was significantly impaired in AA-MSCs. What is more, the cardinal symptoms of AA mice were largely rescued by systemic transplantation of UC-MSCs. Conclusions: Herein, we systematically investigated the signatures and efficacy of MSCs to dissect the alterations occurred in AA both at the cellular and molecular levels. Different from HD-MSCs, AA-MSCs exhibited multifaceted defects in biological characteristics and alterative molecular genetics in the whole genome. Our findings have provided systematic and overwhelming new evidence for the defects of AA-MSCs, together with effectiveness assessments of UC-MSCs on AA as well.

High‐efficient generation of VCAM‐1+ mesenchymal stem cells with multidimensional superiorities in signatures and efficacy on aplastic anaemia mice

“…hUC-MSCs were co-cultured with CD4 + T cells at a ratio of 1:10 as we described before. 2,21 For Th cell analysis, 100 ng/mL Phorbol-12myristate-13-acetate (PMA) (Sigma),1 μg/mL Ionomycin (Sigma) and 2 μmol/L monensin (BD Biosciences) were used to stimulate T cells.…”

Systemic administration of human umbilical cord‑derived mesenchymal stem cells effectively ameliorates the outcomes of a critically ill elderly patient with COVID‑19 with multiple comorbidities: A case report

“…Since the 1960s, MSCs were initially isolated from bone marrow followed by various adult tissues (e.g., adipose tissue and dental pulp) and perinatal tissues (e.g., umbilical cord and placenta), as well as human pluripotent stem cells (e.g., hESCs, iPSCs) (20,(42)(43)(44). Of the aforementioned MSCs, hBM-MSCs and hUC-MSCs are associated with the most applications and long-term in vitro proliferation capacity, respectively (20,24). For decades, the authors of the present study, as well as others, have reported the clinical and preclinical applicability of MSCs in refractory and recurrent diseases, such as Crohn's disease, aplastic anemia, acute myocardial infarction, GVHD and even H5N1-infected pneumonia which cause acute lung injury and acute respiratory distress syndrome (ALI/ARDS), which are similar to the symptoms of SARS-CoV-2 infection (20,24,25,42,43,45).…”

“…Of the aforementioned MSCs, hBM-MSCs and hUC-MSCs are associated with the most applications and long-term in vitro proliferation capacity, respectively (20,24). For decades, the authors of the present study, as well as others, have reported the clinical and preclinical applicability of MSCs in refractory and recurrent diseases, such as Crohn's disease, aplastic anemia, acute myocardial infarction, GVHD and even H5N1-infected pneumonia which cause acute lung injury and acute respiratory distress syndrome (ALI/ARDS), which are similar to the symptoms of SARS-CoV-2 infection (20,24,25,42,43,45). Very recently, Leng et al and Wang et al reported the clinical remission of a 65-year-old female critically ill patient with COVID-19 with hUC-MSC transplantation for 3 times as well, whereas the lung damage was relatively mild, which was confirmed by another studies (14,32).…”

“…Mesenchymal stem/stromal cells (MSCs) possess advantaged immunomodulatory and hematopoietic-supporting properties, together with a multi-lineage differentiation potential; they have been identified from numerous tissues and hold great promise for use in regenerative medicine (20)(21)(22)(23). Generally, the therapeutic effects of MSCs, include immunoregulation and tissue repair, mainly through direct-or trans-differentiation, in an autocrine and paracrine manner, as well as by supplying the microenvironment and homing methods (24)(25)(26)(27)(28). For decades, low-immunogenic MSCs have been shown to be safe and preferable for use in the management of recurrent and refractory diseases, such as spinal injury, type 2 diabetes, graft-vs.-host disease (GVHD), autoimmune diseases and hematological malignancies, as well as for severe influenza H5N1 caused by acute respiratory distress syndrome (ARDS) (20,24,(29)(30)(31).…”

“…Generally, the therapeutic effects of MSCs, include immunoregulation and tissue repair, mainly through direct-or trans-differentiation, in an autocrine and paracrine manner, as well as by supplying the microenvironment and homing methods (24)(25)(26)(27)(28). For decades, low-immunogenic MSCs have been shown to be safe and preferable for use in the management of recurrent and refractory diseases, such as spinal injury, type 2 diabetes, graft-vs.-host disease (GVHD), autoimmune diseases and hematological malignancies, as well as for severe influenza H5N1 caused by acute respiratory distress syndrome (ARDS) (20,24,(29)(30)(31). Recently, Leng et al and Wang et al reported the exploration of adult tissue-derived MSCs upon 7 mild and severe patients and revealed a favorable prognosis (14,32).…”