Phenotypic differentiation of TGF-beta1-responsive pluripotent premesenchymal prehematopoietic progenitor (P4 stem) cells from murine bone marrow.
On the horizon of modern molecular medicine is the requisite technology to capture multipotent human stem cells that are capable of self-renewal and to direct these stem cells along defined lineages for therapeutic purposes. In this article, we describe the hematopoietic and mesenchymal differentiation potential of a unique population of transforming growth factor-beta1 (TGF-beta1)-responsive stem cells derived from murine bone marrow. Stringent selection of the stem cells was accomplished under low serum conditions by virtue of an inherent survival response to a TGF-beta1-vWF fusion protein that was bound to collagen matrices. The TGF-beta1-responsive stem cells initially exhibited a non-adherent and uniformly blastoid morphology, underwent expansion into colonies upon serum reconstitution, and were capable of overt cytodifferentiation along fibrogenic, osteogenic, chondrogenic, or adipogenic lineages upon growth factor stimulation. Remarkably, these stem cells also underwent rapid expansion in the presence of either hematopoietic stem cell factor (SCF) or interleukin3 (IL-3), and differentiated into myeloid and lymphoid phenotypes upon exposure to the latter. Taken together, these results support the hypothesis that pluripotent premesenchymal prehematopoietic progenitor cells, designated P4 stem cells, are present postnatally in murine bone marrow and, thus, may be summarily isolated for various cell-based experimental therapies.
Hall
F L
FL
Gene Therapy Laboratories, Los Angeles, CA 90089-9025, USA.
Han
B
B
Kundu
R K
RK
Yee
A
A
Nimni
M E
ME
Gordon
E M
EM
D017667:Adipocytes / Q000166:cytology; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000235:genetics; D018929:Cell Culture Techniques / Q000379:methods; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology; D003094:Collagen; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007377:Interleukin-3 / Q000494:pharmacology; D008648:Mesoderm / Q000166:cytology / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D010011:Osteocytes / Q000166:cytology; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019089:Stem Cell Factor / Q000494:pharmacology; D017154:Stromal Cells / Q000166:cytology; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*; D014841:von Willebrand Factor / Q000235:genetics
D015815:Cell Adhesion Molecules; D007377:Interleukin-3; C512835:POSTN protein, human; C082838:Postn protein, mouse; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D016212:Transforming Growth Factor beta; D014841:von Willebrand Factor; D004815:Epidermal Growth Factor; D003094:Collagen