Heterogeneity of cell therapy products

Abstract

Cell therapy entails the administration of living cells that have been purified, propagated or differentiated to create a cell product for a specific therapeutic need. [1] The cell therapy industry initially involved only blood transfusion, haematopoietic stem cell transplantation (HSCT) and reproductive in vitro fertilisation, [2] but has now vastly expanded and will soon be one of the therapeutic pillars of healthcare in the 21st century. [2] Cellular therapies have also diversified over the years and many clinical trials are currently underway (https:// clinicaltrials.gov) to assess the safety and efficacy of various cell types for therapeutic use. One of the major cell types being investigated for therapeutic use is stem cells. Stem cells can be defined as a population of undifferentiated cells capable of asymmetric replication in which, with each cell division, one of the cells retains its self-renewal capability while the other enters a differentiation pathway and becomes a mature cell. [3-5] Stem cells can broadly be divided into three categories based on their differentiation potential, namely totipotent, pluripotent and multipotent (Fig. 1). Totipotent stem cells refer to cells with the ability to produce all cell types of the human body, including the placenta. Examples include zygotes and early blastomeres. [6] Pluripotent stem cells, which include embryonic stem cells and induced pluripotent stem cells, have the ability to differentiate into cells of the three embryonic germ layers (ectoderm, endoderm and mesoderm). [6,7] In contrast, multipotent (also called adult or somatic) stem cells are able to differentiate into a limited number of cell types, usually associated with the tissue in which they reside. [3,6] Adult stem cells have been identified in various tissues of the human body. Examples include neural stromal/stem cells, endometrial stromal/stem cells, mesenchymal stromal/stem cells (MSCs) and haematopoietic stem and progenitor cells (HSPCs). [4,8] MSCs have been isolated from bone marrow, the umbilical cord, adipose tissue and dental pulp. [9,10] The main sources of HSPCs are bone marrow, umbilical cord blood (UCB) and mobilised peripheral blood. HSPCs and MSCs are two of the most extensively studied adult stem cells in research and clinical settings. In this review we discuss the heterogeneous nature of HSPCs and MSCs as well as some of the problems associated with the expansion of these cells for use in therapeutic products in various clinical applications. Heterogeneity Adult stem cells exist in a tightly regulated microenvironment (referred to as a niche) and are dispersed between differentiated cells in various tissues in the body. [11] As a result, the isolated cells are a heterogeneous population, consisting of various subpopulations, including a subpopulation of true stem cells. To date, there is no single phenotypic marker that can unambiguously identify a true stem cell. Thus, currently used therapeutic stem cell products are heterogeneous in nature. Another aspect of heterogeneity ...

Key Markers and Epigenetic Modifications of Dental-Derived Mesenchymal Stromal Cells

“…Issues related to cell heterogeneity are getting more and more attention in the field of MSCs research. A more comprehensive understanding of the variability of transplantable populations will help maximize the potential of any MSCs therapy [ 48 ]. According to the International Society for Cellular Therapy, dental-derived MSCs meet all the minimum criteria that define MSCs [ 49 ].…”

Donor Selection is a Critical Component Using Naïve Endogenous Adult Stem Cells for the Treatment of Chronic Diseases and Traumatic Injuries

“…For example, bone marrow is not just hematopoietic cells and MSCs. Bone marrow is composed of hematopoietic cells, e.g., hematopoietic stem cells, RBCs and their respective cell lineages, WBCs and their respective cell lineages, chondroclasts, osteoclasts, vascular tissues, e.g., sinusoids, arteries, arterioles, venuoles, veins, all lined with endothelial cells (inner lining) and smooth muscle cells (outer layer), bone marrow stromal cells, fibroblasts, fibrocytes, adipoblasts, adipocytes, chondroblasts, chondrocytes, osteoprogenitor cells, osteoblasts, osteocytes, telomerase negative stem cells, e.g., MSCs, VSELs, MAPCs, MUSE and telomerase positive stem cells, e.g., MesoSCs, PSCs and TSCs[10][11][12][13][14]17,19,22,23,[28][29][30][31]141,144].Similarly, adipose tissue is not just fat cells and MSCs. White fat adipose tissue is a metabolically active tissue.…”

Ordering and Encapsulation in Viscoelastic Microfluidic Flows

“…These works only present few hectrogentoic variations that are present in tumour cells and many other heterogeneity variabilities are yet to be discovered [181]. Logically, heterogeneities among diseased cells from the same population presents a huge challenge in biology and medicine for diagnostics and treatment [182]. It is critical to understand how such cellular diversity is generated from a single-cell population for example: in cellular expression; homeostasis regulation and, even variations in responses to external stimuli between normal vs diseased tissues.…”