Stem Cell Differentiation Hierarchy: Colony Forming Units and Progenitor Cells
Yes, stem cells can differentiate into colony forming units (CFUs), which represent an intermediate stage between true stem cells and more committed progenitor cells in the hematopoietic differentiation hierarchy. 1
Understanding the Differentiation Cascade
The progression from stem cells to specialized cells follows a hierarchical pathway:
True stem cells possess three defining characteristics: (1) capability for long-term self-renewal and division, (2) unspecialized state, and (3) ability to differentiate into specialized cell types 1
Colony forming units (CFUs) represent an intermediate population that emerges when stem cells begin differentiation. These cells retain significant proliferative capacity and can form colonies when cultured, but have more limited self-renewal compared to true stem cells 2, 3
Progenitor cells are more committed cells with restricted differentiation potential, representing a further stage of lineage commitment beyond CFUs 1
The CFU Stage: Key Characteristics
CFUs occupy a critical position in the differentiation hierarchy:
Mesenchymal stem cells (MSCs) were originally identified as "colony forming units-fibroblastic" because of their ability to adhere to plastic and generate colonies when plated at low density 2, 3
Hematopoietic CFUs can be maintained and expanded in culture with appropriate growth factors. For example, stem cell factor (SCF) combined with IL-3 can increase CFU numbers by nearly 20-fold, including erythroid burst-forming cells, granulocyte/macrophage CFCs, and mixed-cell CFCs 4
CFU-culture (CFU-c) cells represent a population with short-term reconstituting ability and high colony-forming efficiency (approximately 50%), but limited long-term proliferative capacity compared to true stem cells 5
Critical Distinctions in Clinical Context
A major pitfall is the misuse of terminology, particularly calling minimally manipulated cell preparations "stem cells" when they actually contain mixed populations with CFUs and progenitors at low prevalence:
In bone marrow and adipose tissue preparations, only 1 in 1,000 to 1 in 1,000 cells are true stem or progenitor cells capable of differentiation 1
Stem and progenitor cells are the least abundant cell type in minimally manipulated preparations, despite marketing claims 1
The American Academy of Orthopaedic Surgeons emphasizes that this terminology confusion has created substantial problems for patients and physicians 1
Tissue-Specific Examples
Different tissue sources demonstrate this differentiation pathway:
Bone marrow-derived cells: Fractionated populations containing c-kit+ cells or mesenchymal stem cells may provide benefits primarily through indirect biological activities rather than direct differentiation 1
Cardiac-derived stem/progenitor cells: These can emerge as cells expressing specialized markers when cultured under specific conditions, representing the CFU-to-progenitor transition 1
Endothelial colony-forming cells (ECFCs): These are derived from circulating progenitor cells and appear in culture after 7-20 days, forming highly proliferative colonies distinct from mature circulating endothelial cells 1
Practical Clinical Implications
When evaluating cell-based therapies, recognize that:
The presence of CFUs indicates an intermediate differentiation state, not true stem cell populations 3
Colony-forming efficiency remains an important quality assay for cell preparations, but does not guarantee therapeutic efficacy 3
The balance between self-renewal and differentiation of CFU-c can be regulated by extracellular signals, making the microenvironment critical 5